Contributing author: Paul Hockings, Senior Director MR Imaging @ Antaros Medical and Adjunct Professor @ Chalmers University of Technology
Antaros Medical’s journey in kidney imaging started almost 8 years ago, but my own began with my very first imaging project in 1992. Back in 2015, most of Antaros Medical’s projects were in diabetes, obesity, and non-alcoholic steatohepatitis (NASH, now called metabolic dysfunction-associated steatohepatitis or MASH). We were approached by one of our existing customers and asked to investigate potential kidney imaging biomarkers, and we have been working in kidney imaging for drug development ever since.
Today, our capabilities in kidney imaging are extensive. We have learnt a lot about imaging the kidney, delivered many different types of kidney projects for our customers, and are involved in several ongoing research collaborations. In this blog post, I will describe our journey from our initial involvement to where we are now.
In this post I will not go into the specifics of the imaging methods and MRI biomarkers that can add value in kidney drug development. Rather, I would refer you to our recently published review article in the Journal of Clinical Medicine for an overview of these.
It all started with Diabetic Kidney Disease (DKD)
Initially the interest was in diabetic kidney disease (DKD), the term given to chronic kidney disease (CKD) that is associated with diabetes. An estimated 30-40% of patients with type 2 diabetes (T2D) will develop DKD, and this proportion is expected to increase further in line with the growing global prevalence of T2D. Importantly, DKD is the leading cause of kidney failure, requiring kidney replacement therapy of dialysis or transplant.
The ‘gold standard’ for diagnosing DKD has been, and remains, kidney tissue biopsy. Historically this was due to the emphasis on glomerular pathology, however more recently it is because the extent of tubulointerstitial fibrosis seen in a biopsy is the best indicator of disease progression and loss of kidney function. Despite this, kidney biopsy is not commonly performed as the process is highly invasive and carries a risk for patients. There is also susceptibility to sampling bias due to heterogeneity across the kidney.
As such, most DKD patients are generally diagnosed and staged based on the presence and level of albuminuria and the reduction in estimated glomerular filtration rate (eGFR). Albuminuria, an increased level of albumin in the urine, is determined using a spot albumin to creatinine concentration ratio (UACR). eGFR is calculated using a formula based on serum creatinine and/or cystatin C.
Limited biomarkers and limited treatment options
The biomarkers that were (and still are) available for general use, namely UACR and eGFR, are not without their limitations. Albuminuria as determined by UACR is highly variable at an individual level and is sensitive to acute hemodynamic changes. And beyond this, a significant proportion of DKD patients exhibit a non-albuminuric phenotype (sometimes referred to as NADKD). Meanwhile eGFR provides only a rough estimate of kidney damage; significant kidney fibrosis can occur without any detectable change in GFR as the kidney can partially compensate for the loss of nephrons.
Furthermore, before 2020 the treatment landscape for DKD was limited, to say the least. For almost 20 years, there had been no new medicines approved for DKD, and the only treatment option was renin-angiotensin-aldosterone system (RAAS) blockade with either angiotensin-converting enzyme inhibitors (ACE-1) or angiotensin receptor blockers (ARB). However, other (not kidney-specific) medicines were also being used to control hyperglycaemia, manage hypertension, and to reduce albuminuria in DKD patients. There were also very few large-scale clinical trials being initiated in comparison with other disease areas.
All this is to say that the immediate need for novel kidney biomarkers was clear, especially for facilitating drug development in DKD. The existing biomarkers did not provide insights into the underlying pathophysiology or the degree of anatomical damage. As medical imaging was not being used for informing treatment decisions at the time, it was generally not considered diagnostically useful for DKD.
The birth of AM-01, our internal imaging study
Magnetic resonance imaging (MRI) offered an avenue with a lot of potential to overcome the limitations of the existing biomarkers. Using our experience in other disease areas and indications, we began to look into which MRI methods could be applicable for use in the kidney.
In 2015, we designed AM-01, our own internal imaging kidney study, to test a protocol that included a variety of MRI techniques. Some were adapted from use in small, single centre academic studies; some were borrowed from applications other than the kidney; and some had only been done before in healthy volunteers.
AM-01 started in late 2016, and at that time there was no existing data to support the reproducibility of kidney MRI measurements in people with DKD. So, we have been quite thorough in investigating the biological relevance, sensitivity, and specificity, and repeatability of these endpoints. Our findings have been presented at ASN 2018, ERA-EDTA 2019, and ASN 2019, and were published. More recently we have been using the longitudinal follow-up data to look at their predictive value for DKD disease progression, and these results were presented at last year’s ASN and earlier this year at ERA-EDTA.
Involvement in other kidney imaging initiatives
Alongside our own kidney study, we became involved in several other important initiatives and collaborations looking at the use of imaging biomarkers in kidney disease. I will briefly mention some of these below.
In 2017 we joined the PARENCHIMA network (now RENALMRI.org), an initiative with the objective to meet the urgent need for better biomarkers to support the development of effective treatments for CKD. This predominantly involved working to help standardise MRI methods in CKD and contribute to consensus-based recommendations for using these methods in clinical trials.
The East and North London Diabetes Cohort (HEROIC) Study was set up in 2018, and the protocol was designed to investigate the heterogeneity of DKD using renal and cardiac imaging, lab biomarkers, and tissue biopsy. This is an ongoing, 5-year observational study aiming to recruit 500 patients with biopsy-confirmed DKD that are at high-risk of progressing to renal or cardiac events.
The results from Dapagliflozin, Exenatide and Combination for Albuminuria reduction in Diabetes (DECADE) study were published earlier this year. The study was initiated in 2019 to look at furthering our understanding of the mechanisms of action underlying the observed nephroprotective effects of treatment options for DKD.
We then also joined the Biomarker Enterprise to Attack DKD (BEAt-DKD) consortium and more specifically, the iBEAT study. This is a prospective, multi-centre, observational cohort study of 500 patients with early stages of DKD to evaluate the utility of imaging biomarkers.
Future directions for Antaros Medical in the kidney
As for future directions for Antaros Medical in kidney imaging, we will be actively participating in the collaborations and initiatives as described above, but we are also looking forward to expanding our work with our partners on using imaging biomarkers to evaluate treatment effects. For example, we contributed to the protocol design of the REMODEL trial, which is using imaging biomarkers to better understand treatment effects in DKD.
We will also continue working in kidney indications beyond DKD. Take autosomal dominant polycystic kidney disease (ADPKD), for example. Total Kidney Volume (TKV) is currently qualified as a prognostic biomarker by both the US Food & Drug Administration (FDA) and the European Medicines Agency (EMA), which is very promising. Yet there is more that can be done with imaging, such as looking specifically at cyst volume, or haemorrhagic cysts, or functional kidney volume. Lupus nephritis is another disease area where there is a high unmet need for improved biomarkers.
Furthermore, DKD and other kidney diseases are increasingly recognised as highly heterogeneous diseases. Patients have varying clinical characteristics, disease progression, drug responses, and risk of complications. Another interesting path for us is using imaging to identify different phenotypes or stratify patients where existing biomarkers cannot.
A lot of progress has been made in the field since we first started, but we see more opportunities to use imaging to help patients with kidney disease.
In summary
To briefly summarise the Antaros Medical kidney journey:
- Antaros Medical first became involved in the kidney imaging as it offered the potential to overcome many of the limitations of the existing biomarkers in DKD. The unmet need for non-invasive and more sensitive biomarkers was clear from the start.
- We designed our own internal imaging method study, AM-01, to evaluate the utility of different techniques and endpoints.
- Over the years we have become involved in several initiatives and collaborations working to drive forward the use of imaging in kidney disease.
- Future directions for us include continuing to use imaging in the context of treatment effects, expanding further into other kidney indications, and considering how imaging might potentially be used to move kidney care towards precision-medicine.
Blog disclaimer
The views and opinions expressed in this article are solely those of the contributing author/s. These views and opinions do not necessarily represent those of Antaros Medical.
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