A Personalized Microfluidic Model for Kidney Cancer Drug Screening

Image result for A Personalized Microfluidic Model for Kidney Cancer Drug Screening

A new UW Carbone Cancer Center study, published online this week in EBioMedicine, has developed a model that mimics the tumor’s blood supply on a three-dimensional  platform designed in the laboratory of Dr. David Beebe, professor of biomedical engineering and pathology. The authors of the study, led by Drs. Jose “Tony” Jimenez-Torres and Maria Virumbrales-Munoz, used both normal and cancerous tissue from patients to grow the blood vessels. They replicated many of the structures seen in the normal and cancer-tissue blood supplies and used them to test targeted drugs used to treat renal cell carcinoma.

Renal cell carcinoma is the third most common genitourinary cancer in the United States, with about 64,000 new cases each year. This kidney cancer tends not to respond to standard chemotherapy, so anti-angiogenic targeted agents, which can cut off the blood supply to tumors by inhibiting vessel formation, are often used.

“In this type of cancer, clinicians report that giving the patients the wrong drug can be counterproductive,’’ says Virumbrales-Munoz. “You can actually increase angiogenesis and feed the tumor more. This screening approach could help us make treatment decisions for each patient, knowing beforehand the outcome of their treatment.”

Jimenez-Torres says the lab was able to create an in vitro model of each patient’s tumor blood vessels to test the effect of anti-angiogenic drugs. The normalization of tumor blood vessels in response to anti-angiogenic drugs would lead to decreases in tumor size.

“This is the first model for renal cell carcinoma that enables personalized anti-angiogenic drug testing’’ explains Jimenez-Torres.

The preliminary data of this study was so promising that the group was awarded a $1.5 million Cancer Moonshot grant from the National Cancer Institute to compare the results of the personalized model with patient response.

The “moonshot” clinical study will use positron emission tomography (PET) imaging before and after the patients are treated for their cancer, to see whether it responded to a particular drug.  Meanwhile, in the Beebe lab, the tumor tissue will be grown into three-dimensional blood vessel structures and treated with the drugs. The goal is to see whether the in vitro model predicts the patient response.

“Our future goal is not to test every single patient, but to develop a list of markers that will better predict which patient will respond to a treatment,’’ says Virumbrales-Munoz.

Dr. Jason Abel, an associate professor of urology who treats renal cell carcinoma patients, is a collaborator on both projects.

Other Carbone investigators working on the clinical trial include: Drs. Christos Kyriakopoulos, of hematology-oncology; Wei Huang, of pathology; Steve Y. Cho, radiology; and KyungMann Kim, biostatistics.

This article has been republished from materials provided by the University of Wisconsin-Madison School of Medicine Public Health. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:

 Jiménez-Torresa, J. A., et al. (2019). Patient-specific organotypic blood vessels as an in vitro model for anti-angiogenic drug response testing in renal cell carcinoma. EBioMedicine https://doi.org/10.1016/j.ebiom.2019.03.026

Advertisements

To avoid renal ailments, stick to healthy diet, daily workout

Citing that renal ailments are among the top 10 causes for fastest growing causes of death in the world, doctors say that a healthy diet and regular exercise can keep the risk of kidney diseases at bay. “Kidneys are not only responsible for excretion of metabolic waste from the body, but also for maintaining adequate haemoglobin percentage, blood pressure, water content of the body and electrolytes (sodium, potassium),” KIMS ICON Hospital consultant nephrologist and transplant physician Dr. K.R. Mahesh said ahead of the World Kidney Day which will be observed on March 14 (Thursday). The theme for this year is “Kidney health for every one and every where”. “The The objective of the day is to raise global awareness about the existing disparities and inequities of kidney health despite the growing burden of renal ailments worldwide,” Dr. Mahesh said.

Symptoms
Throwing light on the symptoms and complications, he said malfunctioning of one or both kidneys leads to a myriad of problems causing morbidity and mortality. “Kidney dysfunction can be suspected when a person develops symptoms such as swelling of feet, distension of abdomen, puffiness of face, breathing difficulty, froth in the urine, change in colour of urine, burning sensation during urination, difficulty in passing urine and low urine output per day,” Dr. Mahesh explained.

The potential risk for renal dysfunction starts from birth in the form of low birth weight ( less than 2 to 2.5 kg ) either due to pre-term delivery and intrauterine growth retardation (IUGR). Underlining the need for antenatal mothers to have regular check-ups, he said those with history of heart or liver dysfunctions, diabetes, hypertension, obesity, prolonged consumption of painkillers, patients with recurrent urinary tract infections, people living in endemic areas such as in north coastal Andhra Pradesh (Uddanam), Chimakurthy mandal of Prakasam district and Mondupalem near Anakapalle in Visakhapatnam run the risk of getting chronic kidney disease (CKD).

“Regular exercise, healthy diet, drinking clean water, maintaining ideal body weight and avoiding consumption of alcohol and nicotine can prevent the renal ailments,” he added.

Potassium supplements during hot weather may benefit patients with CKD

Image result for Potassium supplements during hot weather may benefit patients with CKD

A study from researchers at the Perelman School of Medicine at the University of Pennsylvania found the risk of mortality is lower for patients with chronic kidney disease when they receive potassium supplements during hot temperature days.

Patients who received the additional potassium saw a 10% drop in mortality, researchers said in a Perelman press release.

Patients with CKD on diuretics are often at risk for low potassium levels, or hypokalemia. That condition can increase the risk of death from cardiac arrhythmias or other causes. While some patients are prescribed combination diuretics that contain both a thiazide and potassium-sparing diuretic, nephrologists and other clinical staff may not be aware that sweating can increase the risk of potassium loss in warmer weather, according to the press release.

“We already know that hot outdoor temperatures are associated with increased risk of heat stroke, dehydration, heart disease, respiratory diseases and higher risk of death overall, but people who take furosemide and have insufficient intake of potassium are at increased risk,” Sean Hennessy, PharmD, PhD, a professor of epidemiology and systems pharmacology and translational therapeutics at Perelman and senior author, said in the release. “As outside temperatures increase, the apparent survival benefit of potassium also increases.”

Nephrologists often prescribe the drug furosemide, a diuretic known commonly as Lasix, to decrease fluid retention and combat swelling in the arms, legs and/or abdomen in patients with heart failure, high blood pressure, and/or kidney and liver disease. The drug, like many other diuretics, causes patients to urinate more than normal, leading to lower levels of potassium in the body. These lower levels can be more dangerous when outdoor temperatures are high, as patients often lose additional potassium through sweating, the release noted.

Researchers for the study looked at 1999 to 2010 data from Medicaid patients in California, Florida, New York, Ohio and Pennsylvania. The data set represented about 40% of total U.S. Medicaid enrollees and made up approximately 20% of the total U.S. population, according to the release. Data were included from those who took furosemide at 40 mg/day or more and had not been prescribed any furosemide nor diagnosed with hypokalemia in the previous year.

Among the 337,885 people who took 40 mg/day or more of furosemide, 32% of them also took potassium when starting the diuretic. The team linked these data to zip code-level daily temperature data from the National Oceanic and Atmospheric Administration and compared two groups — one group included patients who took prescription potassium to prevent hypokalemia when beginning furosemide, and the other included patients who did not take prescription potassium when taking furosemide. The team found that across all temperatures, the potassium-taking group experienced a 9.3% lower risk of death than the group who did not take potassium. This survival benefit was also higher when daily maximum temperatures were higher.

“If this potential relationship between temperature and the survival benefit of empiric potassium is true, it would have important clinical and public health implications,” the authors wrote. “It is well established that high outdoor temperature is associated with increase in mortality and morbidity. Some excess deaths in furosemide users, especially among socioeconomically disadvantaged populations such as Medicaid enrollees in the USA, might be avoidable through interventions to increase potassium intake on hot days. The number of lives saved by such interventions would be expected to increase as global climate change continues.”

The authors speculated that patients with CKD who reside in warmer regions might tolerate increases in temperature better than those in cooler regions.

“Also, a temperature–potassium interaction on mortality, if it exists, might differ across subgroups, such as geographic regions, sociodemographic characteristics including age, comorbidities or degree of frailty. Because we were unable to explore such relationships given the limited number of high-temperature deaths, further research is warranted to investigate these potential relationships in diverse subgroups and health outcomes,” they said.

Lead author Young Hee Nam, PhD, a post-doctoral researcher in biostatistics, epidemiology and informatics, said the study results “do not imply that more potassium is better, and do not imply that prescription potassium may be beneficial for all patients. Further studies are needed to find out the generalizability of our findings to other patient populations. The best way to reduce harmful effects of high temperatures on mortality might be to avoid exposure to high temperatures if possible.” – by Mark E. Neumann

Reference:

http://www.pennmedicine.org/news/news-releases/2019/february/as-temperatures-rise-patients-taking-diuretics-may-see-benefit-from-upping-potassium-intake

Disclosures: This work was supported by the U.S. National Institute on Aging (R01AG025152) and the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102694). The authors report no relevant financial disclosures.

Kidney health for everyone: Focus on prevention

Organ failure can be prevented through routine health examination, lifestyle modification, early diagnosis and treatment. The importance of these can be highlighted by creating awareness

The world’s aim of raising awareness about the increasing burden of kidney diseases worldwide and the need for strategies to prevent and manage them. Besides the heart, trauma, cancer and other organ diseases, kidney diseases are rising alarmingly, and are a major cause of mortality.
At least 2.4 million people die every year due to chronic kidney diseases (CKD) and are now the 6th fastest growing cause of death. Similarly, acute kidney injury (AKI), an important driver of CKD, affects more than 13 million people worldwide. Moreover, CKD and AKI significantly contribute to increased morbidity and mortality from other diseases, such as cardiovascular disease, diabetes, hypertension, obesity, HIV infection, malaria and tuberculosis.

Though the burden of kidney diseases is alarming, this has not yet drawn enough attention. CKD and AKI are often found in people who are born into poverty, face gender discrimination, lack education, and work in hazardous occupations and pollution.

Transplantation is considered the gold standard and most cost-effective treatment of CKD. But it not only requires high set-up costs for infrastructure and a multidisciplinary team of highly specialised manpower, it also cannot be done without organ donors and dialysis backup. Lack of physical facilities and laws as well as cultural bias against organ donation present barriers in countries like ours, making dialysis the default option.

In general, there are national policies and strategies for non-communicable diseases (NCDs) in many countries, but specific policies directed toward screening, prevention and treatment of kidney diseases are often lacking.

Statistics reveal that nearly 3,000 people in Nepal develop kidney failure annually. Similarly, the number of people taking dialysis services across the country is around 4,500, whilst the number of kidney transplants has reached nearly 1,300. The kidney transplant is emerging as the best modality of treatment as it offers a better quality of life than dialysis.

Currently, there are three government hospitals licensed to conduct kidney transplantation. The Shahid Dharmabhakta National Transplant Centre (SDNTC) in Bhaktapur has already conducted 586 kidney transplants over six years with world class results. Likewise, there are nearly 120 patients taking free dialysis services every day. This centre is also the pioneer in liver transplant and brain dead donor kidney transplant in the country, having done six kidney transplants and one liver transplant from three deceased donors till date. Aimed at conducting 200 kidney transplants this fiscal year, the centre has already conducted 161 live donor kidney transplants in the last eight months. This has already saved the country billions of rupees.

Kidney transplantation is tied with strict legal provisions. The old Organ Transplant Act of Nepal allowed only living donor kidney transplantation, and the donor pool was extremely narrow. However, the new Organ Transplant Act of Nepal, 2072 has introduced new provisions, making it more flexible to get donors for transplantation. The three provisions are: Expansion of live donor pool, namely relatives. The second provision is, pair-exchange, where an incompatible donor/ recipient pair is matched with another incompatible donor/ recipient pair for a “swap” from different families.

The third provision is brain-death organ donation and transplantation. One brain-dead person can donate eight solid organs. In Nepal, the number of people sustaining brain-deaths is quite high, especially from road traffic accidents, but due to lack of awareness and various social and religious factors, the rate of brain-death organ donation and transplantation is still low.

Though the main focus of clinical science lies on the curative aspect, it is high time we concentrated on disease prevention. This will reduce the overcrowding of hospitals and grapple with the shortage of human and other resources. Organ failure can be prevented through routine health examination, lifestyle modification, early diagnosis and treatment. The importance of these can be highlighted by creating awareness.

In the last one decade, Nepal has become successful in reaching many milestones in the orbit of transplantation, and there is a lot more to achieve through collective efforts. So the SDNTC, jointly with the Nepalese Society of Organ Transplantation (NESOT) and Indian Society of Organ Transplantation (ISOT), is organising the 1st International Transplant Conference with the theme “Bridging the Gap” on April 20-21 in Kathmandu.

This year’s theme for World Kidney Day “Kidney Health for Everyone Everywhere” calls for universal health coverage (UHC) for the prevention and early treatment of kidney disease.

This can be achieved by adopting a healthy lifestyle through access to clean water, exercise, a healthy diet and tobacco control. Screening for kidney diseases should be made a primary healthcare intervention, including access to identification tools, such as urine and blood tests. And as more resources become available, there is a need for transparent policies governing access to advanced health care services, such as dialysis and transplantation, and better financial protection, such as subsidies

Children on hemodialysis show greater improvements in quality of life post-transplant than those on PD

Image result for pediatric kidney disease

Following kidney transplant, children with ESRD who were on hemodialysis showed greater improvements in quality of life scores than did those who were on PD, according to findings presented at the Annual Dialysis Conference.

“There has been a dramatic decrease in the mortality risk of children with ESRD in recent decades,” Cortney Taylor Zimmerman, PhD, of the department of pediatrics, renal section, at Baylor College of Medicine and Texas Children’s Hospital in Houston, and colleagues wrote. “With increasing life expectancy, there is a need for further research into patient quality of life (QoL) to address the question of whether patients are ‘living well.’ This study is one of the first to longitudinally follow pediatric QoL over time for the same patient and caregiver proxy from chronic dialysis to kidney transplant.”

To examine the change in QoL for pediatric patients from dialysis to transplant, researchers considered responses to the pediatric quality of life inventory 4.0 generic core scales from 19 caregiver/patient dyads (31% were men; aged 2 to 17 years). The questions addressed a variety of measures including physical, emotional and school functioning.

Researchers found patients reported higher overall QoL than did caregivers for both dialysis and transplant and that there were no significant improvements in any of the caregiver response categories. Researchers also found that, although patient self-report scores did not significantly improve after transplant for those who had been on PD (74.8 while on PD vs. 74.9 post-transplant), patients who had been on hemodialysis had increases in total QoL score (75.8 vs. 85.2) and in the health and activity score (75 vs. 87.5). Researchers hypothesized that this may be related to the fact that children on hemodialysis have restricted activity as they are required to go to the hospital three times a week for treatments.

As QoL scores increased for patients who had been on hemodialysis but not for patients who had been on PD, researchers concluded that this study emphasizes “the convenience of home therapies.”

“Further research is needed to examine these findings within a larger population, change in scores over time on transplant, as well as to attempt to better understand potential contributing factors and differences in treatment modalities,” the researchers wrote. “This could lead to the identification of potentially modifiable factors with the goal of improving quality of life and medical outcomes.” – by Melissa J. Webb

Reference:

Zimmerman CT, et al. The Quality of life journey from dialysis to transplant in pediatric end-stage renal disease patients. Presented at the Annual Dialysis Conference; March 16-19, 2019; Dallas.