Discovering New Drugs to Treat Chronic Kidney Disease

Keynote: Drug Discovery for Kidney Precision Medicine

Jonathan Himmelfarb is a leader in kidney research, where he aims to improve chronic kidney disease (CKD) treatment using precision medicine. Himmelfarb explained that developing broad treatment strategies is challenging because CKD is an imprecise term. “We define CKD by a change in the glomerular filtration rate and/or the presence of protein in the urine, but that doesn’t really tell us much about what’s causing that syndrome,” he said. To develop effective therapeutics for CKD, researchers need to understand the specific genetic and environmental factors that influence disease development. Toward this goal, Himmelfarb directs the National Institutes of Health (NIH) Kidney Precision Medicine Project (KPMP), which is designed to create a reference kidney atlas from CKD patient biopsies over an ambitious ten-year timeline. Specific goals of the KPMP include defining disease subgroups, identifying targets for novel therapeutics, and developing personalized treatments for patients. Ultimately, Himmelfarb hopes this project will revolutionize kidney pathology and serve as a community resource for researchers, clinicians, and patients.

How Patients Can and Should Impact Innovation in Kidney Disease

Founder and CEO of Lyfebulb Karin M. Hehenberger has insight into the challenges of living with chronic disease. As a teenager, she was diagnosed with type 1 diabetes, which ultimately required kidney and pancreas transplants. Hehenberger's medical and doctoral training provided the scientific expertise she needed to understand her disease. But after her transplants, she realized the value of her perspective as a patient. “We cannot dismiss the insights and even the solutions coming from those who are living with the disease as potential new product developments,” said Hehenberger, “meaning [that] patients can be innovators.” This insight led Hehenberger to found Lyfebulb, a chronic disease-focused digital platform that connects patients, industry, and investors to enable patient-driven innovation.

Lyfebulb’s strategy for developing patient-focused products.

Currently, Lyfebulb serves ten chronic diseases including diabetes, inflammatory bowel disease, multiple sclerosis, cancer, and addiction. Their uniquely patient-empowered approach has grown a network of 75 patient ambassadors and more than 150 patient entrepreneurs. By providing a bridge between the patient community and leading healthcare companies, Lyfebulb ensures that each product they launch meets a direct need for patients.

Inflammatory Proteomic Signature of Kidney Failure Risk – a Biomarker Path to Drug Development

Monika Niewczas’ lab uses high-throughput sequencing technology to identify determinants of diabetic kidney disease (DKD). Specifically, she seeks to discover novel molecular biomarkers that act as signatures for disease progression. If identified early, these prognostic signatures can inform a personalized treatment approach to improve patient outcomes. To find biomarkers for DKD, Niewczas used a large dataset of blood samples obtained from a cohort of more than 500 diabetic patients studied over a ten-year period in which one-third experienced kidney failure. After examining the patients' plasma proteome, she discovered 17 proteins that were significantly associated with DKD risk. Niewczas named the proteins Kidney Risk Inflammatory Signature (KRIS) proteins, which includes several TNF receptor proteins that had never been identified as prognostic. This work provides a strong foundation to inform drug development approaches and future work aims to intensify efforts to increase our knowledge of molecular biomarkers.

Human Organoid Models of Kidney Disease

Benjamin Freedman uses organoids to model kidney disease and advance drug development. The diverse genetic and environmental factors contributing to kidney disease require advanced models to understand the distinct mechanisms of disease variants. Toward this goal, Freedman has differentiated induced pluripotent stem (iPS) cells into kidney organoids, which function as a miniature version of the kidney. By watching the organoid grow, the Freedman lab can understand kidney development and observe thousands of cells interacting to form specific phenotypes. For complex disease modeling, Freedman obtains patient urinary cells to differentiate into iPS cells, and eventually, personalized kidney organoids. So far, the lab has successfully created models of cystinosis and diabetic nephropathy. They plan to use these platforms to aid novel drug discovery for kidney disease.

Multi-omics Analysis of Diabetic Kidney Disease

Katalin Susztak’s lab uses multi-omics approaches to characterize DKD for precision therapeutics development. The multi-omics approach bridges the gap between genetic variants and disease outcomes by identifying cell types, control regions, target genes, and intermediate phenotypes that ultimately result in kidney disease. Susztak starts by combining eQTL mapping with GWAS datasets to identify genes that likely cause DKD development. One gene, adaptor protein DAB2 in the TGF-β pathway, was identified as a risk factor for DKD. Susztak then conducted single-cell sequencing in the kidney to determine what types of cells expressed DAB2. Across the 70,000 cells examined, Susztak and her colleagues identified 16 distinct cell types as highly expressing DAB2. Finally, they used CKD mouse models to show that reducing DAB2 expression protected mice from CKD development. By examining gene regulation at multiple scales, her research defines a clear role for key genes in DKD.

In Vivo Imaging Tools to Map the Kidney at the Single Nephron Level

Kevin Bennett develops imaging methods to non-invasively and precisely measure kidney structure and function. Current clinical practices to examine kidney function include ultrasounds, biopsies, and glomerular filtration rate measurements. However, these methods lack sensitivity and do not provide early detection for kidney disease. To improve kidney imaging, Bennett developed a novel imaging method in which iron oxide is loaded into ferritin, a naturally occurring protein in mammalian cells, to enable non-invasive MRI imaging.

Individual glomeruli can be detected and tracked in mice following cationized ferritin (CF) injection.

Using this technique, he has detected individual glomeruli in mice and created 3D maps of imaged areas. Further, he can even conduct in vivo tracking of nephrons, the kidney filtering units. Nephron count is completed before birth, can range vastly between individuals, and is thought to influence sensitivity to chronic kidney disease (CKD) later in life.

Immune Tolerance Approaches for Kidney Transplantation

Xunrong Luo studies transplant immune tolerance. In organ and tissue transplantation, the recipient’s body produces an immune response that rejects the “non-self.” Current transplantation techniques aim to prevent rejection by either priming the recipient (chimerism-based tolerance) or suppressing the immune response (non-chimerism-based tolerance). However, chimerism still presents the long-term risk of developing graft-vs-host disease, and non-chimerism weakens the immune system and predisposes the patient to medical problems.

Novel method of transplanting apoptotic donor cells borrows from the immune system’s strategies for self-tolerance.

Luo’s lab has developed a distinct transplantation approach to overcome these issues. In her method, donor cells are rendered apoptotic by a controlled chemical crosslinking process prior to implantation into the recipient. She tested the validity of this approach in a transplantation of islet cells from one mouse to another. She was surprised at how clear the effect was: nearly 100% of recipients did not reject the transplant over more than 100 days of monitoring. Since then, her lab has also successfully transplanted hearts and kidneys in mice. Ultimately, Luo hopes to translate this strategy into clinical practice.

New Strategies for Diabetic Kidney Disease

Katherine Tuttle’s research centers on improving treatment for CKD. She recently led clinical trials investigating the inhibition of sodium/glucose co-transporter 2 (SGLT2) to reduce the risk of adverse cardiovascular disease events in type 2 diabetes patients. It quickly became evident that SGLT2 also improved the kidney health of patients. To explore this phenomenon, she conducted another trial to examine SGLT2 for CKD treatment specifically. When administered alongside standard-of-care ACE inhibitors or ARBs, patients with and without pre-existing CKD experienced significant benefits. Specifically, SGLT2 inhibition reduced risk of albuminuria, eGFR decline, end stage kidney disease, and even mortality. “This was the first clinical trial in the field of nephrology that was ever stopped early for overwhelming benefit,” said Tuttle. She hopes that these agents will become widely utilized in the clinic to improve patient outcomes in the future.

Genomic Medicine for Kidney Diseases

Ali Gharavi studies the genetic architecture underlying kidney disorders. In particular, his lab uses whole exome sequencing (WES) to understand the vast diversity within CKD. Although there are useful clinical predictors for kidney disease such as family history, novel strategies like WES aim to diagnose CKD cases of unknown origin. In using WES to diagnose patients with CKD, Gharavi was surprised to discover that 17% of cases were of unknown etiology. At that moment, Gharavi realized this was a useful way to consider “diagnoses in these patients who are very frustrated not knowing why they developed kidney failure.” In one application of WES, a 57-year-old patient of Gharavi’s, newly diagnosed with kidney disease, revealed a dominant Alport syndrome diagnosis. Treatment involved a new clinical trial, which allowed at-risk family members to be quickly screened. Gharavi anticipates WES's continued application will improve future diagnoses, understanding of risk factors, and family screening.