Human Kidney Organoids Underscore Importance of Microenvironment in Polycystic Kidney Disease

MedicalResearch.com Interview with:
Benjamin Freedman, Ph.D
.
Assistant Professor | University of Washington
Department of Medicine | Division of Nephrology
Member, Kidney Research Institute
Member, Institute for Stem Cell and Regenerative Medicine
Seattle WA 98109 

MedicalResearch.com: What is the background for this new technology and study? What are the main findings?

Response: Polycystic kidney disease (PKD) is the leading genetic cause of end stage renal disease, affecting approximately twelve million people. The hallmark of the disease is the massive expansion of kidney tubules into large, fluid-filled cysts. Although we know the genes that are mutated in this disease, we do not have a firm grasp on what they do to protect the body from disease.

We used a new system, human kidney organoids with gene-edited PKD mutations, to discover how factors outside the cell affect cyst formation. We found that liberating the organoids from plastic dishes into floating cultures greatly increased the number and size of cysts that formed. We also found that PKD organoids had problems in their ability to change the shape of collagen scaffolds surrounding them, compared to control organoids of the same genetic background.

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Loss of Sense of Smell, Malnutrition Common in Kidney Disease Patients

MedicalResearch.com Interview with:

Dr. Nigwekar and Dr. Paunescu

Dr. Nigwekar and                 Dr. Paunescu

Teodor Paunescu, PhD and
Sagar Nigwekar, MD
Division of Nephrology
Massachusetts General Hospital

 MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Over 25 million people in the U.S. have chronic kidney disease, and the number of deaths caused by this disease has doubled between 1990 and 2010. It is projected that by 2030 more than 1 in 3 adults over 65 years old will be diagnosed with chronic kidney disease.

Many patients with kidney disease are also malnourished, which negatively impacts their quality of life, overall health, and even survival. However, no effective treatments are currently available to address malnutrition in these patients.

The sense of smell plays an important role in determining food flavor. If a patient’s ability to smell is impaired, this could affect the taste of food, for example, foods that used to appeal to the patient may no longer do so. Given the relation between the sense of smell and appetite, we set out to investigate the loss of smell in patients with kidney disease, and to test an intervention aimed at alleviating their smell deficits.

Our first goal was to determine if patients with various degrees of kidney disease suffer smell losses and whether smell issues might affect their nutritional status. We found that, while most kidney disease patients do not perceive a problem with their sense of smell, deficits in the ability to smell are actually common among these patients, and the severity of these deficits increases with the severity of their kidney disease. Moreover, our study found that reductions in several markers of nutrition (such as cholesterol and albumin levels) correlate with the impairment in these patients’ sense of smell.

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Marked Increase in Number of US Patients With Kidney Stones

MedicalResearch.com Interview with:
Li Hao Richie Xu MD

Division of Mineral Metabolism
University of Texas Southwestern Medical Center
Dallas, Texas, United States

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Over the past three decades, the prevalence of the kidney stones has escalated in the United States. Changes in dietary patterns, increasing body weight and obesity likely contributed to this significantly higher prevalence of kidney stone. In this study, we explored temporal changes in stone composition, demographic characteristics, and in serum and urinary kidney stone risk profile in kidney stone forming population for the last 35 years.

The proportion of uric acid stones has been almost doubled during this period. Although age and body mass index (BMI) increased over time in both uric acid and calcium stone formers, uric acid stone formers were consistently older, had higher BMI, and lower urinary pH than calcium stone formers. In addition, over time, the proportion of female vs. male increased in calcium stone formers, but not in uric acid stone formers. The most significant urinary parameter differentiating uric acid stone formers from calcium stone formers is 24-hour urinary pH.

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Tamsulosin (Flomax) Improves Passage of Some Kidney Stones

MedicalResearch.com Interview with:
Ralph Wang, MD, MAS

Associate Clinical Professor, Department of Emergency Medicine
University of California, San Francisco

MedicalResearch.com: What is the background for this study?

Response: Medical expulsive therapy, most notably tamsulosin, has been studied extensively to improve stone passage in patients diagnosed with ureteral stone. Prior trials and meta-analyses have identified a benefit. In fact, tamsulosin is
recommended by the American Urologic Association for patients diagnosed with ureteral stones < 10mm that do not require intervention. However, recent well-conducted multi-center randomized trials have not found any improvement in stone passage.

Thus we conducted a systematic review and meta-analysis of all double blinded, placebo controlled randomized trials of tamsulosin to determine whether it improves stone passage.

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Researchers Search for Probiotic Factors To Reduce Risk of Calcium Oxalate Kidney Stones

MedicalResearch.com Interview with:

Dr. Hatim A. Hassan Section of Nephrology, Department of Medicine The University of Chicago Chicago, IL 60637

Dr. Hatim A. Hassan

Dr. Hatim A. Hassan MD PhD
Section of Nephrology, Department of Medicine
The University of Chicago
Chicago, IL 60637

MedicalResearch.com: What is the background for this study?

Response: Nephrolithiasis is the second most prevalent kidney disease in USA after hypertension, with a rising prevalence and complications including advanced chronic kidney disease (CKD) and end stage renal disease (ESRD). It remains a major source of patient discomfort and disability, lost working days, and health-care expenditure, with an annual economic cost approaching $10 billion. Hyperoxaluria is a major risk factor for kidney stones (KS), and 70-80% of KS are composed of calcium oxalate. Urinary oxalate is an important determinant of supersaturation, and the risk for stone formation is affected by small increases in urine oxalate. Oxalate is a metabolic end product that cannot be further metabolized and is highly toxic. The mammalian intestine plays a crucial role in oxalate homeostasis, by regulating the amount of absorbed dietary oxalate and providing an avenue for enteric oxalate excretion. Anion exchanger SLC26A6 (A6)-mediated intestinal oxalate secretion plays a critical role in preventing hyperoxaluria and calcium oxalate kidney stones (COKS). Inflammatory bowel disease patients have a significantly increased risk of kidney stones due to the associated enteric hyperoxaluria. Obesity is a risk factor for KS and obese stone formers often have mild to moderate hyperoxaluria. Hyperoxaluria is also emerging as a major complication (developing in > 50% of patients) of bariatric surgery for obesity. With the rising prevalence of obesity and increased utilization of bariatric surgery, it is expected that the incidence of hyperoxaluria and related COKS (including the associated cost burden) will continue to increase at a significant rate. Primary hyperoxaluria (PH) is an inherited disease in which there is endogenous oxalate overproduction, which leads to recurrent KS and/or progressive nephrocalcinosis, ESRD, as well as significant hyperoxalemia, systemic oxalosis and premature death. Systemic deposition of calcium oxalate (oxalosis) leads to bone disease, cardiac arrhythmias, cardiomyopathy, skin ulcers, erythropoietin refractory anemia, and digital gangrene. The only treatment known to fully correct the underlying metabolic defect is liver transplantation or combined kidney-liver transplantation once ESRD develops. In addition, significant hyperoxalemia is also seen in ESRD. Cardiovascular diseases are the leading cause of morbidity and mortality in ESRD patients, and a recent report raised the possibility that the ESRD-associated hyperoxalemia might contribute to this increased risk. Lowering serum oxalate might improve cardiovascular outcomes in ESRD patients if these findings are confirmed.

Unfortunately, there is currently no specific therapy that effectively lowers urine and/or plasma oxalate level(s), and the risk of recurrent COKS, nephrocalcinosis, oxalate nephropathy, ESRD, & systemic oxalosis remains substantial in the absence of treatment.

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Fruit Extract Hydroxycitrate Shows Promise As Potential Therapy To Prevent Kidney Stones

MedicalResearch.com Interview with:

Dr-Jeffrey-RimerJeffrey D. Rimer PhD
Ernest J. and Barbara M. Henley Associate Professor
University of Houston
Department of Chemical and Biomolecular Engineering
Houston, TX 77204-4004

MedicalResearch.com: What is the background for this study?

Response: This project’s origin can be traced back to preliminary results obtained by Dr. John Asplin at Litholink Corporation revealing an organic acid, hydroxycitrate (HCA), was a promising inhibitor of calcium oxalate monohydrate (COM) crystallization. COM is a principle component of human kidney stones. Interestingly, HCA is a molecular analogue of citrate (CA), the current therapy for stone disease. My research group at the University of Houston began collaborating with Dr. Asplin to explore the effects of HCA in more detail. We conducted in vitro assays using two techniques: bulk crystallization studies to quantify HCA efficacy and more detailed in situ atomic force microscopy (AFM) studies to assess the growth of COM crystal surfaces in real time.

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Excessive Intake Non-Dairy Protein Could Raise Risk of Kidney Stones

MedicalResearch.com Interview with:

Pietro Manuel Ferraro, MD MSc PhD Assistant Professor Fondazione Policlinico Universitario A. Gemelli Catholic University of the Sacred Heart Senior Collaborator in the Nurses' Health Study Brigham and Women's Hospital Channing Division of Network Medicine

Dr. Ferraro

Pietro Manuel Ferraro, MD MSc PhD
Assistant Professor
Fondazione Policlinico Universitario A. Gemelli
Catholic University of the Sacred Heart
Senior Collaborator in the Nurses’ Health Study
Brigham and Women’s Hospital
Channing Division of Network Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In our study, we looked at the association between dietary intake of different sources of protein (vegetable, dairy and non-dairy animal), potassium (a marker of fruits and vegetables) and their interaction and the risk of forming kidney stones. We looked at their interaction because some protein is a source of acid, whereas fruits and vegetables are a source of alkali, thus their relationship could potentially impact acid-base status and in turn the risk of stones by modifying the metabolism of calcium and other elements such as urine citrate and uric acid.

We found that the risk of forming stones depends not only on the amount of protein but also on the source, with no risk associated with intake of vegetable and dairy protein, and a modestly higher risk for excessive non-dairy animal protein; on the other hand, intake of potassium was associated with a markedly lower risk. Interestingly, the interaction between intake of protein and potassium, the so called net acid load, was also associated with higher risk of forming kidney stones, suggesting that the effect of acid intake is modulated by that of alkali and vice versa.

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Multiple Kidney Stones Linked to Increased Coronary Artery Calcium

MedicalResearch.com Interview with:
Dr. Ryan Hsi MD
Clinical Fellow, UCSF Medical School and
Mathew Sorensen, MD, MS
Residency Program Director
Department of Urology
University of Washington
Director, Comprehensive Metabolic Stone Clinic
Puget Sound VA

MedicalResearch.com: What is the background for this study?

Response: Kidney stones affect 1 in 11 people, and the incidence is rising.  When kidney stones pass, they can be very painful, and if they obstruct urinary flow as they pass, they can be a cause of kidney injury and sepsis.  It is well-known that kidney stones are associated with diseases such as coronary artery disease, obesity, diabetes, and hypertension.  Less well established is the relationship with kidney stones and pre-clinical markers of these diseases.  That is, before a person has a heart attack, a person may develop atherosclerosis first – are kidney stones associated with these early warning signs of future disease?

MedicalResearch.com: What are the main findings?

Response: This study evaluated the association of coronary artery calcium and kidney stones.  Coronary artery calcium is a measure of calcification of the blood vessels that supply the heart, and it is a predictor of future cardiovascular events.  Our study of the Muli-Ethnic Study of Atherosclerosis evaluated individuals who had coronary artery calcium measured and compared those who had a history of none, one, or multiple kidney stones.  We found that individuals who had a history of multiple kidney stones were associated with higher levels of coronary artery calcium.

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Calcium Supplements Linked To Increased Risk of Kidney Stones

MedicalResearch.com Interview with:
Christopher Loftus M.D. candidate
Cleveland Clinic Lerner College of Medicine

Medical Research: What is the background for this study? What are the main findings?

Response: Most kidney stones are made, at least partially, of calcium composite. In a prospective study of nurses in the post-menopausal age, it was found that diets that contained high amounts of calcium were beneficial in preventing kidney stones in this population. In the gut, calcium can bind to oxalate which prevents it from being absorbed into the body and decreases the concentration of calcium in the urine. However there has been debate as to whether supplemental calcium (calcium pills) has the same beneficial effects as calcium in the diet. Supplemental calcium enters the gut in large quantities all at once so it may enter the blood stream in higher concentrations over smaller amounts of time. By the same token, vitamin D plays a role in the management and balance of calcium in the body and could potentially have an effect on stone formation as well.  It has also been debated whether vitamin D supplementation has major effect on patients who are known to be stone formers.  So we reviewed CT scans of patients and 24 hour urine collections (both male and female of adult age) who were known to have kidney stones and measured the growth of stones over a period of time.

Our main findings were that supplementary calcium increased the rate of stone formation in these patients. We also found that vitamin D had a protective effect and patients taking only vitamin D had a slower rate of stone progression.

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No Association Between Kidney Stones and Osteoporosis or Fractures in Women

Monique Bethel, MD Subspecialty Service, Department of Veterans Affairs Medical Center, Department of Medicine, Section of Rheumatology Georgia Regents University Augusta, GAMedicalResearch.com Interview with:
Monique Bethel, MD
Subspecialty Service, Department of Veterans Affairs Medical Center,
Department of Medicine, Section of Rheumatology
Georgia Regents University
Augusta, GA

MedicalResearch: What is the background for this study?

Dr. Bethel: Osteoporosis and kidney stones share several risk factors, including elevated calcium in the urine (hypercalciuria), low potassium intake, and possibly, diets high in sodium. Accordingly, several studies have shown a significant relationship between kidney stones and osteoporosis in men. However, it is unclear if this relationship is also true for women. Previous studies examining this association have been small and inconclusive.   With the Women’s Health Initiative, we had data available from approximately 150,000 postmenopausal women in the US. Using this database, we were able to study the relationship between kidney stones and changes in bone mineral density and fractures.

MedicalResearch: What are the main findings?

Dr. Bethel: We found no association between the presence of kidney stones and changes in bone mineral density over time at the hip, lumbar spine, or the whole body. Also, there was no association between the presence of kidney stones and fractures. We also found that 14% of women who had a history of kidney stones upon entering the studies had another one occur during the course of the study (approximately 8 years).

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Ultrasound Able To Reposition and Facilitate Passage Of Kidney Stones

Dr. Michael Bailey, Ph.D. Senior Principal Engineer Assistant Professor, Mechanical Engineering and Adjunct Assistant Professor, Urology University of WashingtonMedicalResearch.com Interview with:
Dr. Michael Bailey, Ph.D.
Senior Principal Engineer
Assistant Professor, Mechanical Engineering
and Adjunct Assistant Professor, Urology
University of Washington

Medical Research: What is the background for this study? What are the main findings?

Dr. Bailey: Ultrasonic propulsion is a new technology that uses focused ultrasound energy to reposition kidney stones transcutaneously. We report the findings from the first human investigational trial of ultrasonic propulsion toward the applications of expelling small stones and dislodging large obstructing stones. Subjects underwent ultrasonic propulsion either awake without sedation or during ureteroscopy while anesthetized. A pain questionnaire was completed before, during, and after propulsion for awake subjects. Potential adverse events were assessed weekly for 3 weeks after propulsion for all subjects.

The primary outcome was to reposition stones in the collecting system. Secondary outcomes included safety, controlled movement of stones, and movement of stones < 5 mm and ≥ 5 mm. Stones were localized and repositioned in 14 of 15 enrolled subjects. Of the 43 targets, 28 (65%) showed some level of movement while 13 (30%) were displaced to a new location > 3 mm. No adverse events were reported. Mild discomfort during the procedure was rare, brief, and self-limited. Stones were moved in a controlled direction with over 30 fragments being passed by most patients who previously had a lithotripsy procedure. The largest stone moved was 10 mm. One patient experienced pain relief during treatment of an obstructing stone. In 4 subjects a seemingly large stone, which might have required surgery, was determined to be a cluster of small passable stones.

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Kidney Stone Risk Affected By Age and Sex

MedicalResearch.com Interview with:
Majuran Perinpam, BsC

Mayo Clinic
Rochester, Minn

MedicalResearch: What is the background for this study?

Response: The four key urinary factors: Calcium, magnesium, oxalate and uric acid are all implicated in kidney stone formation. Age and sex are known to influence kidney stone risk and type (1). However the effects of demographics on excretion of the four key urinary factors are not clear. Since diet alters urinary excretions of the four factors, adjusting for this is important. During metabolic evaluation of kidney stone patients, these urinary factors are often measured in 24-hour urine samples. However, often a single adult reference range is used and the effect of demographics is rarely taken into account during the interpretation of results.

MedicalResearch: What are the main findings?

Response: From a cohort of 709 healthy individuals we found a substantial influence of age and sex on the excretion of urinary calcium. Adjusted models showed that urinary calcium, magnesium, oxalate and uric acid were all less in females, possibly explaining why kidney stones are more dominant in males (1). Also a positive association of urinary uric acid excretion with Cystatin C eGFR, but not eGFR calculated from creatinine, suggests cystatin C to possibly being involved in inflammation and hyperuricemia. But further studies are needed to investigate this.

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High Fluid Intake Reduces Risk Of New Kidney Stones

Wisit Cheungpasitporn, MD, Nephrology Fellow Program director: Suzanne Norby, MD Project mentors: Stephen B. Erickson, MD and John C. Lieske, MD Departments of Nephrology and Hypertension Mayo Clinic, Rochester, MNMedicalResearch.com Interview with:
Wisit Cheungpasitporn, MD, Nephrology Fellow
Program director: Suzanne Norby, MD
Project mentors: Stephen B. Erickson, MD
and John C. Lieske, MD
Departments of Nephrology and Hypertension
Mayo Clinic, Rochester, MN

 

MedicalResearch: What is the background for this study?

Dr.Cheungpasitporn: Kidney stones are very common urologic problems. In addition, once someone has a kidney stone, the likelihood of having another episode increases to 50% within 5 years. Increased fluid intake has been suggested as a simple strategy for kidney stone prevention. However the data on conclusions regarding the benefit, adherence and safety of high fluid intake for the primary or secondary prevention of stones were limited. Thus, we conducted this meta-analysis to evaluate the treatment effect of high fluid intake on the incidence of kidney stones, and to assess the compliance and safety of high fluid intake to prevent kidney stones. Our data presented at the National Kidney Foundation’s 2015 Spring Clinical Meetings may help improve clinicians’ ability to manage kidney stones.

MedicalResearch: What are the main findings?

Dr.Cheungpasitporn: Our meta-analysis included 9 studies with 273,954 patients. According to the findings of our study, individuals with daily high fluid intake (to achieve a urine volume of at least 2.0‒2.5 L per day) had lower risk of new kidney stones by approximately 50%. High fluid intake provided the same benefit in men and women. In addition, high fluid intake reduced the risk of recurrent kidney stones by 40%. Overall, high fluid intake is safe with low adverse events.

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Cafffeine Intake Associated With Reduced Kidney Stone Risk

Pietro Manuel Ferraro, MD PhD Candidate Division of Nephrology Catholic University of the Sacred Heart Rome ItalyMedicalResearch.com Interview with:
Pietro Manuel Ferraro, MD PhD Candidate
Division of Nephrology
Catholic University of the Sacred Heart
Rome Italy

Medical Research: What are the main findings of the study?

Dr. Ferraro: We analyzed the association between caffeine intake and the risk of developing kidney stones in three large cohorts of U.S. health professionals. The 217,883 participants included did not have any history of kidney stones when follow-up began. During 20 years of follow-up, 4,982 of them developed a kidney stone. In all three cohorts, participants with higher intakes of caffeine had a reduced risk of developing kidney stones. Intake of caffeine from sources other than coffee was also associated with reduced risk of kidney stones. Among 6,033 participants with 24-hour urine data, intake of caffeine was associated with higher excretion of calcium but also higher urine volume and lower likelihood of calcium and uric acid stone formation. Continue reading

Ultrasound Equal To CT As First Test For Kidney Stone Diagnosis

Rebecca Smith-Bindman, MD Professor in the Departments of Radiology; Epidemiology and Biostatistics; and Obstetrics, Gynecology and Reproductive Medicine UCSF San Francisco Calif.MedicalResearch.com Interview with:
Rebecca Smith-Bindman, MD
Professor in the Departments of Radiology;
Epidemiology and Biostatistics; and Obstetrics, Gynecology and Reproductive Medicine UCSF San Francisco Calif.


Medical Research: What are the main findings of the study?

Dr. Smith-Bindman: New technology is rapidly developed in medicine, and its important to understand how that technology should be used to improve patient health outcomes. Sometimes the technology is far better than existing technology and it should replace the earlier technology, and sometimes it is not and therefore should not be used. In this clinical scenario – I e. patients who present to an emergency department with abdomen or back pain thought to possibly reflect kidney stones, ultrasound is a simpler, less expensive , and more readily available test in the emergency department setting and therefore if it is equal to CT with respect to patient outcomes, it should be used as the first test in these patients. Currently, CT is the test widely used for patients with suspected kidney stones.

We assessed a large number of patients with suspected kidney stones seen at one of 15 large academic emergency medicine departments across the country. Patients were assigned to point of care ultrasound performed by an ED physician, radiology ultrasound or radiology CT. We assessed a broad range of patient centered outcomes and found each of the three tests we studied were equivalent in terms of these outcomes including complications related to missed diagnoses, related serious adverse events, time spent in the emergency department and repeated ED visits and hospitalizations. However, the exposure to ionizing radiation was around half as high in patients who underwent ultrasound as their first test, and thus ultrasound should be used as the first imaging test in patients with suspected nephrolithiasis.
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Kidney Stone Risk Rises With the Temperature

Gregory Tasian, MD, MSc, MSCE Attending Urologist The Children’s Hospital of Philadelphia MedicalResearch.com Interview with:
Gregory Tasian, MD, MSc, MSCE
Attending Urologist
The Children’s Hospital of Philadelphia 

 

Medical Research: What are the main findings of the study?

Dr. Tasian: The risk of developing kidney stones increased during the study period in all the cities except Los Angeles when mean daily temperatures rose above 50°F (10°C). Mean daily temperatures reaching 86°F (30°C) were associated with risk increases of 38% in Atlanta, 37% in Chicago, 36% in Dallas, and 47% in Philadelphia compared with 50°F (10°C). Kidney stone risk peaked within 3-5 days of exposure to high temperatures but then decreased within 7 to 10 days afterward.

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Kidney Stones: Non-Invasive Treatment Not Always Better

Charles D. Scales, Jr MD MSHS Assistant Professor of Surgery Division of Urologic Surgery Duke University Medical CenterMedicalResearch Interview with:
Charles D. Scales, Jr MD MSHS
Assistant Professor of Surgery
Division of Urologic Surgery
Duke University Medical Center

 

MedicalResearch: What are the main findings of the study?

Dr. Scales: When it comes to treating kidney stones, less invasive is not always better.

We used the best method short of a randomized trial to balance out patients in terms of factors that might influence the success of treatment.  In other words, we achieved a “statistical toss-up” for factors that could influence the outcome of the procedure.

When we balanced out all of the factors that might influence the chance of a repeat procedure, we found that about 11% of patients treated with non-invasive SWL had a repeat procedure, as compared to <1% with minimally invasive URS.
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Kidney Stones : Marker of Increased Heart Disease Risk in Women?

Dr. Pietro Manuel Ferraro Division of Nephrology–Renal Program, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli Hospital, Rome, ItalyMedicalResearch.com Interview with Dr. Pietro Manuel Ferraro
Division of Nephrology–Renal Program, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli Hospital, Rome, Italy


MedicalResearch.com: What are the main findings of the study?

Dr. Ferraro: We analyzed three large cohorts over time to see if those with prevalent or incident kidney stones might have a higher risk of developing coronary heart disease (fatal or non fatal myocardial infarction or the need for coronary revascularization). The cohorts consisted of over 200,000 participants without any prior history of coronary heart disease. After a median follow-up of over 8 years, we observed that women affected with stones seem to have a greater risk of developing coronary heart disease independent of a number of other known cardiovascular risk factors such as diabetes or high blood pressure. We did not observe a significant association among men. Continue reading