Alport Syndrome Alport Syndrome is a genetic condition that causes progressive kidney disease, potential hearing loss, and problems with vision. There are three types: X linked Alport Syndrome (XLAS), autosomal recessive Alport Syndrome (ARAS), and autosomal dominant form (ADAS). The first step in understanding this diagnosis is learning all you can about it. The more you know, the more options you have to live a healthy and productive live. We will walk you through this, explaining exactly what Alport Syndrome is, what a person with this diagnosis can expect, and what first steps you should begin taking. There is good news. There are now treatment plans with can reduce the effects of this disease while providing greater overall health. We’ll cover these as well, including what you can do right now to begin helping yourself or your loved one. As you learn more about this disease, and what treatments are available, the less overwhelmed you will feel. Please keep reading, you will find important information that will help you cope with this diagnosis, along with useful resources that can assist you in this difficult journey. What is Alport Sydrome? Alport Syndrome is a genetically inherited disease of the kidneys (passed down through the family). It is caused by genetic mutations of the collagen IV family of proteins. These proteins are a major part of tissue structures called basement membranes that are present in all tissues including the kidney, inner ear, and eye. Genetic mutations of collagen IV cause thinning and splitting of the glomerular basement membrane. Ultimately, this process causes scarring throughout the kidney, and over time may leads to kidney failure. It may also causes abnormalities in the ears and eyes which can lead to vision and hearing loss. affect the inner ears and eyes. What are the Symptoms of Alport Syndrome? [Below is a list of symptoms associated with Alport Syndrome. Not all will be present, and some symptoms will only show up as the disease progresses. But in all cases, the kidneys will be affected. You should make a list of any symptoms you suspect and provide them to your physician. These, along with the test results, will help to confirm the diagnosis, and provide for a more effective treatment plan.] Symptoms of Alport Syndrome may include: Hematuria (blood in urine) Abnormal urine color Proteinuria (large amounts of protein “spilling” into the urine) Edema (swelling in parts of the body, most noticeable around the eyes, hands and feet, and abdomen) Foamy urine Low blood albumin levels Decreased or loss of vision (more common in males) Flank pain Loss of hearing (more common in males) High cholesterol in some cases High blood pressure in some cases Tendency to form blood clots if spilling large amounts of protein Kidney failure in only some cases as the disease progresses How is Alport Syndrome Diagnosed? A diagnosis of Alport Syndrome is considered in a person with kidney issues (blood and/or protein in urinalysis). Blood in the urine is almost always present in affected individuals. Hearing loss can also be present, so hearing tests can help with the diagnosis. As vision can be effected by this disease, visual screening is a very important tool in diagnosing and managing this disease. A kidney biopsy can also be helpful in diagnosing Alport Syndrome as biopsy slides can show a thinning of the glomerular basement membrane. Kidney biopsies can also show an absence of collagen tissue and can be tested for the presence presence of specific genes (COL4A3, COL4A4, and COL4A5). This information can even sometimes determine the specific genetic form of the disease. Because Alport Syndrome is an inherited disease, genetic testing will confirm the diagnosis, even when there are no other symptoms present. Your healthcare provider will ask you about your family medical history. They may also order the following tests to help make a diagnosis. Urine Test: To determine protein levels and blood in your urine. Blood Tests: To analyze certain chemical factors such as creatinine and cholesterol. Glomerular Filtration Rate: This will determine how well your kidneys are functioning. Kidney Biopsy: To check for specific damage to the kidneys. Hearing Test: To see if any hearing loss has occurred. Vision Test: To see if vision has been affected. Genetic Test: This will confirm the diagnosis even when the other tests are inconclusive, and determine the specific type of Alport Syndrome present Finding the Right Team It is important to find the right medical professionals when seeking treatment for this medical condition. As this is a rare disease, it might be difficult to find doctors experienced with Alport Syndrome. So it is vital to seek out professionals who have extensive experience treated patients with this disease. A team of specialists can provide a comprehensive plan to treat all aspects of this disease, while providing emotional support for the family. How is Alport Syndrome Treated? Treatment will consist of controlling the various symptoms and slowing the progression of kidney disease. It is very important for people with Alport Syndrome to be seen regularly by a nephrologist (physician who specializes in kidney disease) to monitor the effects of the disease. Patients should be on a medication that slows the progression of kidney damage. These medications are called ACE-inhibitors (angiotensin converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers). High blood pressure can be controlled with hypertension medication. These medicines can have the added benefit of slowing the damage occurring within the kidneys. Diuretics can help reduce swelling. Statin drugs will help control high cholesterol. As additional studies are done, new treatments will be made available. Regular vision and hearing evaluation is also important. It is important to have your eyes checked by an ophthalmologist who is aware of your condition. While most eye problems associated with this disease are not serious, regular exams will help maintain eye health and good vision. Alport Syndrome can lead to hearing loss in many patients. Regular checkups with an audiologist is recommended to monitor any hearing problems that might arise. For a person with Alport, it is particularly important to protect against noise exposure, as this will cause additional hearing loss. Males are twice as likely as females to experience hearing loss. Fortunately hearing aids can help with improve hearing. Your nephrologist may also recommend: Diuretics to help eliminate excess fluids in the body Low Sodium diet helps to control edema Anticoagulants to prevent blood clots Blood Pressure medications to lower high blood pressure Statins to lower the cholesterol level Maintaining a healthy diet: Correct amounts of protein and fluid intake according to your nephrologist’s recommendations. A healthy diet consists of low salt with emphasis on fruits and vegetables, low in saturated fat and cholesterol. Exercising Not smoking Vitamins Genetic Counseling How to Help Yourself or a Loved One Fear, anger and frustration are a few of the emotions that you will experience when learning how to live with this disease. It is very important to have a support system in place to help work through these difficult emotions. Sit down with your family and talk about this disease. Let them know what to expect, and how they can help. Let the person with the diagnosis know you are available to talk, reassure them that you are there for them. Family support is important, but it will be critical during these times: During the initial diagnosis Difficulties or changes in treatments Significant declines in health or well being During times of added stress There are support groups that can provide emotional support along with helpful information. The most important thing you can do is provide a caring and supportive environment for the person with this disease. Feeling all alone at times is normal, but knowing there is a support system of caring people willing to listen will go a long way in maintaining emotional health. This disease requires professional treatment. We encourage you to contact us today so we can begin evaluating your specific form of Alport Syndrome, and develop a treatment plan tailored to your specific needs. The Alport Syndrome Research Collaborative developed Clinical Practice Recommendations aimed at standardizing therapy for children with Alport Syndrome. Guidelines for treatment of adult Alport Syndrome patients are also available (1).
NephCure Funded Research 2022 2022 NephCure Award Recipients NEPTUNE Grant Awardees Ana C. Onuchic-Whitford, MD (Brigham and Women’s Hospital) Discovering the landscape of allele-specific expression in the human kidney Ana Claudia Onuchic-Whitford, MD, is a nephrologist at Brigham and Women’s Hospital and an Instructor in Medicine at Harvard Medical School in Boston, MA. She received her M.D. from the University of São Paulo in Brazil, where she also worked in a basic oncology laboratory and completed residency in Internal Medicine. After relocating to the U.S., she repeated her Internal Medicine residency at the University of Connecticut and completed a five-year clinical and research fellowship in adult nephrology in the joint Brigham and Women’s Hospital / Massachusetts General Hospital program. Impressed by how genetics revolutionized medicine and motivated to find missing diagnoses for kidney disease patients, she became interested in searching for genetic determinants of kidney disorders. From a research standpoint, Ana joined Boston Children’s Hospital (BCH) as a post-doctoral research fellow to study the genetics of nephrotic syndrome and chronic kidney disease of unknown etiology in the Hildebrandt lab. Her current research in computational genomics with the Sampson Lab at BCH aims to identify imbalances in gene expression and find novel mechanisms of gene regulation that can contribute to glomerular disease. From a clinical perspective, Ana helped establish the Kidney Genetics & PKD Clinic at Brigham and Women’s Hospital. She now leads this clinic and directly cares for over 100 patients with genetic kidney diseases, including genetic FSGS, Alport Syndrome, polycystic kidney disease, and congenital kidney anomalies, among other inherited nephropathies. In addition to advancing the field of glomerular diseases and nephrotic syndrome, the potential to bridge the science to both genetics-driven patient care and to education in genomic literacy is a valued aspect of her research in computational genomics. Lay Summary of the Project: Description: During the genetic revolution of the last two decades, important discoveries have revealed the major role of genetic factors in kidney function, development and disease. Humans have tens of thousands of genes, which are segments of DNA that guide how our bodies function. Hundreds of forms of chronic kidney disease have been shown to be caused by defects in single genes – including more than 60 genes for nephrotic syndrome (NS), a clinical condition in which the kidneys lose a large amount of protein. As genetic knowledge has transformed the understanding of kidney disease, we are moving to personalized, genetics-guided clinical kidney care. However, many patients with suspected genetic kidney disease still do not have a diagnosis, and the mechanisms by which some genetic factors cause disease are still obscure. In this setting, different genetic studies are needed, including one called allele-specific expression (ASE). An allele is a copy of a gene: for almost all of our genes, there are two copies (two alleles) – one that we received from our mother, and one received from our father. The DNA sequence of a gene is used to create mRNA, a molecule that serves as an intermediate for the subsequent production of a protein. By analyzing someone’s mRNA sequences, we can often identify specifically from which of the two gene copies (two alleles) the mRNA molecules originated from. When performing ASE analysis, we calculate the number of mRNA molecules (collectively called “gene expression”) originating from each of the two alleles: if the number is the same, this is called balanced expression. However, if most of the mRNA comes from one specific allele, this is called “allele-specific expression.” ASE has already been shown to contribute to several illnesses, including autism, heart disease and cancer. For example, in a person who has one normal gene copy and one defective gene copy, if the expression is skewed towards the defective allele, this person may have more severe disease. From a kidney standpoint, a prior study by our group found that individuals with NS had ASE of NPHS1 – a gene responsible for the production of nephrin, a very important component of the kidney filter. However, ASE studies in human kidney disease are limited. Goals and Significance: In this project, our goal is to identify occurrence of ASE in the kidney filtering units (glomeruli) of individuals from the Nephrotic Syndrome Study Network (NEPTUNE). We believe that discovering skewed expression of certain genes can help identify new genetic mechanisms contributing to kidney disease, urine protein loss and NS. To this end, we will search for ASE of genes known to cause NS, when mutated. We will then look for genes that have greater ASE in NEPTUNE participants, compared to healthy kidney samples. Next, we will search for which locations within the DNA are causing the imbalance in mRNA. Finally, we will overlap this with a database that shows which DNA regions are actively being used by each kidney cell type. This can allow us to pinpoint where in the kidney the ASE is happening. In summary, our study seeks to identify ASE occurring in kidneys of patients with significant urine protein loss (e.g., NS) and use this data to identify new pathways leading to kidney disease. We also aim to make this ASE information available to all researchers through an online portal, to contribute to more studies and, hopefully, to future clinical diagnostic and treatment strategies. CureGN Pilot Project Grant Awardees Rosemary V. Sampogna, M.D., PhD & Simone Sanna-Cherchi, M.D. (Columbia University Irving Medical Center/Vagelos College of Medicine in New York) Patient-derived kidney organoids to study mechanisms and therapeutics in Mendelian forms of FSGS Rosemary V. Sampogna, M.D., Ph.D. Dr. Sampogna is an Associate Professor in the Division of Nephrology at Columbia University Irving Medical Center / Vagelos College of Medicine in New York. Her research is focused on the molecular and genetic mechanisms that specify kidney architecture and ultimately determine function, on the role of cadherins during nephrogenesis, and on the role of the circadian clock as a developmental timer that determines the rate of branching and organogenesis. More recently, her work has been directed at studying the functional consequences of human mutations using vertebrate and cellular models, including patient-derived induced pluripotent stem cells (iPSC) and organoids. Simone Sanna-Cherchi, M.D. Dr. Sanna-Cherchi is an Associate Professor in the Division of Nephrology at Columbia University Irving Medical Center / Vagelos College of Medicine in New York. His main area of research involves the genetics of rare forms of kidney diseases and their complications, with special focus on congenital anomalies of the kidney and urinary tract (CAKUT) and nephrotic syndrome caused by minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). His work spans the entire spectrum of genomics research, including genome-wide association studies and large-scale sequencing approaches for rare variants association. To complement his sequencing and genotyping approaches for human traits, he has developed new mouse models for congenital defects of the urinary tract and nephrotic syndrome. With the support of the NephCure – CureGN Pilot Project Grant Award we plan to generate a panel of iPSCs derived from CureGN participants who carry mutations in FSGS Mendelian genes. These cell lines will allow us to generate patient-specific kidney organoids. These models will allow to study the effect of mutations of key regulatory genes for podocyte development, structure, and function in the patient’s genomic and epigenomic context. We hope that our studies will help develop new therapeutic approaches for these devastating conditions. Update: Dr. Sanna-Cherchi and Dr. Sampogna, with this support, have generated patient-derived induced pluripotent stem cells (iPSCs) from children and young adults carrying causal variants in FSGS-associated genes such as TRIM8, TRPC6 and others. They are studying the effect of these variants in iPSC-derived 3D kidney organoids using a multiomic approach that leverages on simultaneous interrogation of single nucleus transcriptomic and open chromatin signatures, coupled with proteomics studies. The ultimate goals of this project are to identify gene-specific molecular mechanisms that might lead to precise drug targeting approaches. See Awardees From Other Years: 2021 2022 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2009 2008
Everything You Need to Know About Travere’s New Clinical Trial for Children, EPPIK September 2, 2021 by Kylie Karley Travere Therapeutics has recently launched their Phase 2 pediatric clinical trial, EPPIK (Evaluating Problematic Proteinuria in Kids) which is aimed at helping children with FSGS, MCD, IgAN and other rare kidney diseases. We know that with a clinical study specifically designed for kids, parents and caregivers may have some questions. We asked Travere to answer some of these questions and have complied an FAQ list for our community around EPPIK. What is the EPPIK study? EPPIK (Evaluating Problematic Proteinuria in Kids) is a Phase 2 study of children 1-17 years old with focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), IgA nephropathy (IgAN), also known as Berger’s disease, IgA vasculitis (IgAV), also known as Henoch-Schönlein purpura, or Alport syndrome (AS). These rare kidney diseases are associated with progression to end-stage kidney disease and currently have limited or no treatment options. This study aims to further understand if an investigational therapy, sparsentan, can help the kidneys filter protein and slow the decline of kidney function. The amount of protein found in the urine (called proteinuria) is seen as a marker of kidney function. Lowering proteinuria levels is associated with better kidney health outcomes. What is sparsentan? Sparsentan is a novel Dual Endothelin Angiotensin Receptor Antagonist (DEARA) – this means it is a dual acting, highly selective antagonist of both the endothelin A receptor (ETAR) and the angiotensin II subtype 1 receptor (AT1R). In the EPPIK Study, sparsentan is taken once a day orally. What is a Phase 2 study? A Phase 2 study is a clinical trial that helps researchers determine how safe, tolerable and effective an investigational drug may be in specific patient populations, such as those noted above. While the EPPIK study is a Phase 2 study, sparsentan has been studied in another Phase 2 study as well as two Phase 3 studies involving approximately 880 patients (some of whom were children). The purpose of the EPPIK study is to gain further experience on the use of sparsentan in children. How long does this study take? Patients who meet all eligibility criteria and are enrolled in the study may expect to participate in the study for about 2 years and 3 months. Will you be enrolling children with congenital Nephrotic Syndrome or infantile Nephrotic Syndrome? Yes, children ages 1-17 with one of those syndromes who meet the study criteria will be able to participate in the EPPIK Study. The specific disorders we are looking for are noted above in the answer to question 1. How many children and young people are you looking to enroll in this study? We will be looking to enroll approximately 57 children in the EPPIK study. How many study sites are there available? Where are these sites located? Sites will be in the United States, UK, and various countries in the EU (France, Germany, Italy, Spain, Netherlands, Poland, Sweden). The final list of sites has not been fully determined yet. Because this study is for children, how is it different than a study for adults? The main difference is how much blood is drawn from the children to do all the tests necessary to evaluate sparsentan in the study. Patient safety is always our number one priority, and, with children, we won’t sample as much blood as we would from an adult. We narrowed the number of tests and worked with the central lab to be able to get results from a smaller sample size. We also must ensure that we adequately inform both the child who might participate in the study and the child’s parents/guardians about all the requirements the study has as well as any risks that may be associated with participating in the study. We do this by developing different study assents or ways to communicate what the study entails so that participating families understand the purpose of the study and what is involved. Are you asking kids about the taste, smell, etc. of the study drug? Yes, we will be asking the children to answer simple questions on how the drug tastes, smells, feels, etc. How do you determine which participants will be required to have pregnancy testing or take birth control? We realize this is a delicate subject for some children and their parents, but it is very important that any female child who has had her first menstruation period take birth control according to the protocol. This class of drugs is known to potentially cause harm to a developing fetus, and therefore we do not want any female participant who is able to have a child to become pregnant. Is there flexibility where lab samples can be collected for my child? Is there an option for home care visits to collect these samples? Yes, there is some flexibility in where labs are taken. If the child can’t make it to the clinical site to have the labs drawn, which is always the preferred way, we have contracted with a company that will come to the patient’s home or other convenient location, to draw the labs and send them in for testing. Does my child have to stop the medications they’re on? What drugs can they remain on? That depends, if they are enrolled in this study, they will need to stop any drug that functions similarly to the investigational drug. That is, if they are on an ACE inhibitor or ARB, they will need to stop those drugs at least 2 weeks before they begin taking the experimental drug and will not be able to take them while they are participating in the study. They will be able to continue with certain blood pressure medications if not in the same drug class, as well as many other medications they may be on. The Investigator will have a complete list of drugs that are allowed and not allowed. What will happen to the results of this clinical study? After all the patients have been enrolled and have completed the study, the data will be analyzed to see if it was successful in reducing the amount of protein in the urine and if it slowed the decline in kidney function as measured by estimated glomerular filtration rate, or eGFR. How well the drug was tolerated, that is, the safety profile, will also be analyzed. Those results will, in all likelihood, be put into a document known as a manuscript and published in a scientific journal. Data will also be added to the study listing on the clinicaltrials.gov website at the end of the study. If my child is in another trial studying sparsentan, do they have to enroll in this new study? If so, will their study site change? No, if your child is participating in another trial with sparsentan they would not be eligible to join the EPPIK study. They would stay in the study they are currently in. For more information about EPPIK, contact medinfo@travere.com
A Day in the Life of a Nephrologist: 2021 NephCure Patient Summit April 20, 2021 by Kylie Karley Have you ever wondered what it might be like to walk in a kidney specialists’ shoes for a day? Get a rare peek ‘behind the curtain’ and hear from actual nephrologists about their perspective on treating rare kidney patients, some of their daily challenges, and tips for making the most of your appointments. Join us Sunday, May 16th from 12-4pm ET for the 2021 NephCure Patient Summit. During this FREE virtual gathering of patients from around the globe, you’ll hear about the latest in research and treatments and learn about your disease. You’ll also have the opportunity to directly ask our experts questions and participate in interactive community roundtables. The “Day in the Life of a Nephrologist” panel will feature Drs. Jason Cobb, Michelle Rheault, and Suneel Udani. The Patient Summit will also offer you the chance to hear from other NephCure specialists, NephCure staff, and regional volunteer leaders. Meet the Panelists: Dr. Jason Cobb is an assistant professor of medicine in the Emory University Division of Renal Medicine. Dr. Cobb is a graduate of Morehouse College with a BS in biology. He holds a medical degree from Emory University School of Medicine and completed his internal medicine residency and nephrology fellowship at Emory University. He is board-certified in internal medicine and nephrology. He sees patients in nephrology clinic at Emory University Hospital Midtown in the Medical Office Tower seeing patients with nephrology complaints such as chronic kidney disease due to diabetes, hypertension, vascular disease, and glomerulonephritis. Also, Dr. Cobb takes care of hemodialysis patients at Emory Dialysis Greenbriar and Emory Dialysis Northside, and home dialysis patients at Emory Dialysis Northside. He also rounds on inpatient services at Emory University Hospital Midtown and Emory University Hospital. Research and teaching interests include quality improvement and nephrology fellow clinic at Grady Memorial Hospital. Dr. Michelle Rheault is a board certified pediatric nephrologist and Associate Professor of Pediatrics. She completed her Pediatric Nephrology fellowship at the University of Minnesota in 2006 followed by a research fellowship at Mount Sinai School of Medicine in New York City. She joined the faculty at the University of Minnesota in 2008 and is currently the Director of the Division of Pediatric Nephrology and Medical Director of the Pediatric Dialysis unit. She is on the steering committee of the Pediatric Nephrology Research Consortium, a clinical research network that aims to facilitate collaboration in pediatric nephrology. Her clinical and research interests include Alport syndrome and other genetic kidney diseases, pediatric glomerular disease, and pediatric end stage kidney disease. Dr. Suneel Udani is a native of Chicago’s western suburbs. He joined Advanced Renal Care in July 2011. He completed his undergraduate, Master’s in Public Health, and medical school degrees at Northwestern University and went on to do his Internal Medicine training at the University of Chicago and the University of Pittsburgh. He served as a Chief Medical Resident at Cook County Hospital prior to returning to the University of Chicago for his fellowship in Nephrology. Dr. Udani is the author of multiple peer-reviewed journal articles and has presented his research at national conferences and is the author of multiple text book chapters on diagnosis and management of kidney disease. His focus is on glomerular disease and heart-kidney interactions. He is also a clinical investigator for community-based renal research program and a dedicated educator and advocate for patients with kidney disease. To learn more about the 2021 NephCure Patient Summit, including a full list of speakers, and full event agenda, click here.
Alessia Fornoni, M.D., Ph.D Professor of Medicine and Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine Email: afornoni@med.miami.edu Dr. Alessia Fornoni is a tenured Professor of Medicine and Molecular and Cellular Pharmacology at the University of Miami Miller School of Medicine. She is the Chief of the Katz Family Division of Nephrology and Hypertension and serves as and Director and Chair of the Peggy and Harold Katz Drug Discovery Center. She is also the Associate Director of the MSTP program. In 2013, Dr. Fornoni gained experience in drug development as Global Head of Discovery in Cardiovascular and Metabolism at Hoffman-La Roche in Basel. She is currently the Vice President and Chief Scientific Officer of L&F Health LLC, a small start-up company focused on finding a cure for patients affected by chronic kidney diseases. As a physician-scientist who has maintained a resolutely focused research program that has provided novel and seminal contributions to our understanding of the pathogenesis of kidney disease, her research is supported by grants from National Institutes of Health, industry and private foundations. She has received prestigious awards: among them, she is the first female nephrologist in the history of the University of Miami to become a member of ASCI. She serves on the editorial board of the Journal of Clinical Investigation, Diabetes and Kidney International. She was visiting professor at more than 50 academic institutions and international meetings worldwide. She serves as grant reviewer for NIH, DOD, ADA, AHA, UK-diabetes, NephCure and Alport foundations, Cariplo foundation and the Italian Ministry of Health. She currently serves on the advisory board of more than 10 companies. Her contributions have been published in high impact journals: Journal of Clinical Investigation, NEJM, Nature Medicine, Science Translational Medicine, Journal of Biological Chemistry, Diabetes among others. She successfully trained several graduate students and post-doctoral fellows and was recipient of the best graduate school mentor of the year award in 2016. Her trainees are occupying key academic and industry positions in five different continents worldwide. Through her pioneering work on insulin signaling, cholesterol metabolism and sphingolipid-related pathways, Dr. Fornoni uncovered novel pathogenetic mechanisms and therapeutic approaches for glomerular disorders. Her internationally recognized research findings, which are now being translated into humans with novel therapeutic applications, have challenged existing paradigms and have dramatically altered the research direction in these areas. She also invented a cell-based assay that is currently being utilized for high content screening of drug libraries and for the stratification of patients with kidney disease. Moving forward, her vision is one that brings industry, investors and not for profit organizations around the table with the intent to match science with innovation and patients’ motivation to find a cure for kidney diseases. Selected Publications Mitrofanova, Alla & Drexler, Yelena & Merscher, Sandra & Fornoni, Alessia. (2020). Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS. Journal of cellular signaling. 1. 56-69. 10.33696/Signaling.1.013. Ge, Mengyuan & Fontanesi, Flavia & Merscher, Sandra & Fornoni, Alessia. (2020). The Vicious Cycle of Renal Lipotoxicity and Mitochondrial Dysfunction. Frontiers in Physiology. 11. 732. 10.3389/fphys.2020.00732. Murphy, Shannon & Mahan, John & Troost, Jonathan & Srivastava, Tarak & Kogon, Amy & Cai, Yi & Davis, T. & Fernandez, Hilda & Fornoni, Alessia & Gbadegesin, Rasheed & Herreshoff, Emily & Canetta, Pietro & Nachman, Patrick & Reeve, Bryce & Selewski, David & Sethna, Christine & Wang, Chia-shi & Bartosh, Sharon & Gipson, Debbie & Tuttle, Katherine. (2020). Longitudinal changes in health-related quality of life in primary glomerular disease- results from the CureGN study. Kidney International Reports. 10.1016/j.ekir.2020.06.041. Liu, Xiaochen & Ducasa, Gloria & Mallela, Shamroop kumar & Kim, Jin-Ju & Molina, Judith & Mitrofanova, Alla & Wilbon, Sydney & Ge, Mengyuan & Fontanella, Antonio & Pedigo, Christopher & Santos, Javier & Nelson, Robert & Drexler, Yelena & Contreras, Gabriel & Hassan, Al-Ali & Merscher, Sandra & Fornoni, Alessia. (2020). Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport Syndrome. Kidney International. 10.1016/j.kint.2020.06.040. Abou Daher, Alaa & Francis, Marina & Azzam, Patrick & Ahmad, Anis & Eid, Assaad & Fornoni, Alessia & Marples, Brian & Zeidan, Youssef. (2020). Modulation of radiation-induced damage of human glomerular endothelial cells by SMPDL3B. The FASEB Journal. 34. 10.1096/fj.201902179R. Weinstock, B. & Feldman, David & Fornoni, Alessia & Gross, Oliver & Kashtan, Clifford & Lagas, Sharon & Lennon, Rachel & Miner, Jeffrey & Rheault, Michelle & Simon, James. (2020). Clinical trial recommendations for potential Alport syndrome therapies. Kidney International. 97. 10.1016/j.kint.2020.02.029. Defreitas, Marissa & Katsoufis, Chryso & Infante, Juan & Granda, Michael & Abitbol, Carolyn & Fornoni, Alessia. (2020). The old becomes new: advances in imaging techniques to assess nephron mass in children. Pediatric Nephrology. 10.1007/s00467-020-04477-8. Freedman, Barry & Moxey-Mims, Marva & Alexander, Amir & Astor, Brad & Birdwell, Kelly & Bowden, Donald & Bowen, Gordon & Bromberg, Jonathan & Craven, Timothy & Dadhania, Darshana & Divers, Jasmin & Doshi, Mona & Eidbo, Elling & Fornoni, Alessia & Gautreaux, Michael & Gbadegesin, Rasheed & Gee, Patrick & Guerra, Giselle & Hsu, Chi-Yuan & Brennan, Daniel. (2019). APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale. Kidney international reports. 5. 278-288. 10.1016/j.ekir.2019.11.022. Ducasa, G. & Mitrofanova, Alla & Fornoni, Alessia. (2019). Crosstalk Between Lipids and Mitochondria in Diabetic Kidney Disease. Current Diabetes Reports. 19. 10.1007/s11892-019-1263-x. Otalora, Lilian & Chavez, Efren & Watford, Daniel & Tueros, Lissett & Correa, Mayrin & Nair, Viji & Ruiz, Philip & Wahl, Patricia & Eddy, Sean & Martini, Sebastian & Kretzler, Matthias & Burke, George & Fornoni, Alessia & Merscher, Sandra. (2019). Identification of glomerular and podocyte-specific genes and pathways activated by sera of patients with focal segmental glomerulosclerosis. PLOS ONE. 14. e0222948. 10.1371/journal.pone.0222948.
NephCure Funded Research: Dr. Alessia Fornoni May 27, 2017 by Lauren Eva NephCure Funded Research: Dr. Alessia Fornoni Dr. Alessia Fornoni is a physician scientist focused on better treating and one day, curing individuals with FSGS and other diseases that cause Nephrotic Syndrome. Early in her research career, she received a grant from NephCure, which enabled her to identify a new gene that plays a role in Nephrotic Syndrome. Her breakthroughs in research today could lead directly to a cure for FSGS. Recently, she shared with us her recollections of that experience and what receiving that grant meant for her work. -NKI I grew up on a goat farm in Italy. When I was 8, a local physician buying cheese at our farm encouraged my parents to send me to school in a nearby city. It was there that I first set my sights on becoming a doctor. Medical school brought me to the United States where, after several years in research, I became a nephrologist. Early in my nephrology training, I was fortunate to receive funding from NephCure. The grant I received from NephCure truly catapulted my career and solidified my interest in glomerular diseases like FSGS. In 2008, as a young investigator at the University of Miami, my NIH-funded research was focused on diabetic kidney disease. One day, I was approached by the Chief of Kidney and Pancreas transplantation, Dr. George W. Burke, who shared with me interesting results he gathered when utilizing rituximab in patients with post-transplant proteinuria. His findings sparked my interest—Why did a drug that was used primarily to treat cancer by depleting immune cells also seem to improve these patients’ kidney disease? I decided to investigate this phenomenon further. Dr. Alessia Fornoni With my team, I studied 27 individuals with primary FSGS who received kidney transplants. We were able to prove that preventive treatment with rituximab can reduce the chance of recurrence of proteinuria in patients with FSGS after their kidney transplant. This was groundbreaking. We hoped that our data could help patients with kidney failure due to FSGS, who are tragically at a 30-80% risk of redeveloping the disease after a kidney transplant. At this point, I knew that a new study was needed to confirm my findings and to demonstrate the direct mechanisms by which rituximab may protect the kidney. I had more questions and knew that there was more to learn. But without additional funding, I would not have been able to continue. I turned to NephCure Kidney International. Supporters like you have helped NKI create a research award program, open exclusively to glomerular disease researchers who have a focus on finding a cure for affected families and patients. Through this program, I applied for and received a Bridge Grant that allowed me to continue my work on rituximab. Because of this funding from NephCure, we made significant advancements in the field.We created a screening that enabled us to predict which patients would develop recurrent FSGS after their transplant. We also identified a new gene (SMPDL3b) that plays a role in Nephrotic Syndrome. This gene can now be targeted and used to help create new drug treatments. These discoveries give other researchers in this field building blocks to learn more about FSGS, potentially leading to additional breakthroughs. Before our discoveries with rituximab, I was primarily focused on diabetic kidney disease. Today, due in part to funding from NephCure which advanced my work, I have developed a strong interest in studying rare glomerular diseases, like FSGS. And like me, when you look at a list of the top glomerular disease researchers in this field, many of them received funding or other support from NephCure at some point in their career. Your donation to NephCure makes a difference. For me personally, you have allowed me to reach breakthroughs in my work on FSGS and other glomerular diseases. Can you make a donation today to ensure that research into Nephrotic Syndrome and FSGS can continue? Your gift can help support scientists early in their career, as I once was, who need additional support to study these rare kidney diseases. My battle to find a cure for patients with glomerular disease continues today. Recently, I discovered that a compound called hydroxypropyl beta cyclodextrin (HPβCD) may have benefits in the treatment of certain types of kidney disease. HPβCD has already shown promising pre-clinical results and is now being developed by Variant Pharmaceuticals to treat FSGS. I am hopeful about its potential to delay the progression of this chronic and often times debilitating disease. Thank you for your support thus far in our journey, and thank you for working alongside me in our joint effort to eliminate FSGS and other diseases that cause Nephrotic Syndrome. Together, I know that one day soon, we will find a way to eliminate the suffering caused by this condition. With gratitude, and with the commitment to work with you in finding a cure and training the next generation of physician scientists, Alessia Fornoni, MD, PhD Alessia Fornoni, MD, PhD, is a professor of medicine at the University of Miami Miller School of Medicine, the Peggy and Harold Katz Family Chair, the Director of the Peggy and Harold Katz Family Drug Discovery Center, and the newly named chief of The Katz Family Division of Nephrology and Hypertension. Dr. Fornoni’s research, which has been NIH-funded for the past 10 years, focuses on podocytes and mechanisms of proteinuria, lipid biology, insulin signaling, drug development, and target identification. Her clinical interests are in the area of diabetic kidney disease and of rare glomerular disorders, such as focal and segmental glomerulosclerosis, and Alport syndrome. As a mentor, Dr. Fornoni has trained more than 20 pre- and postdoctoral research fellows, several of whom have gone on to faculty or academic/research positions. She has published more than 90 original articles and is an internationally known lecturer.
Other Glomerular Diseases Primary glomerular disease means that the condition occurs on its own, without another known systemic disease such as lupus or diabetes. These diseases are also known as idiopathic (having no known cause), and cause Nephrotic Syndrome. There are many similarities in symptoms and treatment options of all forms of Nephrotic Syndrome. However, each type of primary Nephrotic Syndrome listed below has disease specific distinctions. Click below to read more specifically about each. Alport Syndrome C1q Nephropathy IgM Nephropathy Membranoproliferative Glomerulonephritis (MPGN)
Proteinuria Resource Center Proteinuria (pro-teen-yur-EE-uh) is an early warning sign of chronic kidney disease (CKD). In some cases, there are no signs or symptoms to warn about early kidney disease. It can take months or years for symptoms to become obvious, and many of the symptoms are non-specific and even temporary. Because of this, many people are unaware they may be at risk for serious health problems. This is not a diagnostic site, but rather an informational one that is designed to encourage people to have better discussions with their doctors. What is proteinuria? Proteinuria is the name used by medical professionals when a large amount of protein, or albumin, that should remain circulating in a person’s blood is “spilled” into their urine and eliminated from the body. Proteins are large molecules that our bodies need to function properly. Proteinuria can also be referred to as albuminuria. Proteinuria indicates the kidneys filtering units are not functioning properly. Some pregnant women have higher than normal levels of protein in their urine, and taking certain medications can also trigger higher than normal protein loss. It is not always serious, but it should NOT be ignored. Proteinuria has been also known to occur in people with cancer, diabetes, heart disease, or excessive weight gain, as well as those with a chronic kidney problem. However, much high levels of protein in the urine is serious. A cause of the proteinuria must be found and the goal of treatment should be to stop or lower the amount of protein as soon as possible to prevent permanent kidney damage. What are the risk factors for proteinuria? The two most common health conditions associated with proteinuria are diabetes and high blood pressure. Both diabetes and high blood pressure can cause damage to the kidneys, which can lead to proteinuria. Kidneys can also become damaged in other ways, such as from: Medications Injury Poisons Infections Immune system disorders Rare kidney diseases such as: Nephrotic Syndrome Minimal Change Disease Focal Segmental Glomerulosclerosis Membranous Nephropathy MPGN C3G C1q Nephropathy IgA Nephropathy IgM Nephropathy Alport Syndrome Other risk factors include: Obesity Being over 65 years of age Family history of kidney disease Preeclampsia (high blood pressure and proteinuria during pregnancy) Race and ethnicity What are the signs and symptoms of proteinuria? Signs and symptoms include: Edema: Swelling of the body, especially around the face, hands, and feet Rapid weight gain Foamy or bubbly urine High blood pressure Feeling tired Sometimes there are no signs or symptoms at all Blood with normal amounts of protein keeps your body’s fluids in balance. Kidneys that are not working properly by spilling protein will cause fluid to leak into your body’s tissue and cause swelling. This is usually seen around the eyes, in hands and feet and in your belly (abdomen). This swelling is called edema and is a common symptom associated with proteinuria. Edema is not the same as normal weight gain. People with proteinuria may gain a lot of weight, but it is as a result of the untreated kidney problem and fluid retention. A large amount of protein in your urine may make it look frothy, foamy, have lots of bubbles, or have a funny color. People with proteinuria may have trouble breathing or feel fatigued due to the strain on the body caused by underlying kidney problems and fluid retention. These signs of large protein loss indicate the possibility of a kidney problem. Proteinuria can be discovered during a routine doctor’s visit through a simple urine sample. Further laboratory testing is the only way to find out whether the protein in a person’s urine is significant. What can proteinuria lead to? If the underlying problem that causes proteinuria is left untreated, a person is at risk for developing more serious kidney problems. The kidneys can loose some of their function or even stop working. End-stage renal disease (ESRD) is the last step in the disease process. Long term dialysis or a kidney transplant are the only treatment options to replace lost kidney function. What is Nephrotic Syndrome, and how does it relate to proteinuria? Nephrotic Syndrome is the name medical professionals give to a group of symptoms that suggest a serious kidney problem. Nephrotic Syndrome is not a disease, but a collection of symptoms that can be caused by any one of several diseases. Proteinuria is one of the most important signs (or laboratory findings) that suggest a person could have Nephrotic Syndrome. What can your test results mean? It is important that you talk with your doctor if you have symptoms or a laboratory test result that may suggest you have proteinuria. Testing can help a doctor make a correct diagnosis, but you need to manage your own health care actively. You can determine your level of proteinuria using our Proteinuria Calculator. Urine Protein to Creatinine Ratio (UPCR) or Albumin to Creatinine Ratio (ACR) Tests A UPCR test, also known as an ACR test, is performed through a urine sample and is used to quickly and simply estimate the amount of protein being spilled into the urine. While small amounts of protein in the urine is normal, large amounts can indicate the risk for kidney disease. A normal UPCR/ACR test result is less than 30 mg/g. Levels between 30 – 300 mg/g are considered moderate levels of proteinuria. UPCR/ACR levels of protein greater than 300 mg/g are considered severe proteinuria, and a patient should consult with a kidney specialist called a nephrologist. It is important to understand that patients with severe levels of protein being spilled into their urine should seek treatment immediately. Your top priority should be to: Ask your kidney specialist to help figure out what is causing the protein in your urine. Make sure your specialist is aggressively treating your condition in order to stop or slow the amount of protein spilling into your urine. Monitoring your condition is not aggressively treating. Please assume that while you have severe levels of proteinuria, your kidneys are actively being damaged. If you don’t feel you are being treated aggressively, consider seeking a second opinion. Visit our NephCure Specialists page to see if there are any NephCure-approved kidney care experts near you. NephCure Kidney International is a patient advocacy organization and is not licensed to practice medicine. The information on this site is intended to be educational and not diagnostic or recommended treatment. Consult with your doctor if you learn anything that might alarm you or if you have any questions. NephCure thanks Questcor Pharmaceuticals for its support of the Proteinuria Resource Center.