We know that PSMA functions as a transmembrane glycoprotein with both folate hydrolase and carboxypeptidase capabilities. On the other hand, we know that kidney plays an important role in the metabolism of proteins and peptides for absorption, transport and degradation. We know that PSMA is expressed on the brush border of proximal tubular cells, so it is hypothesized that it functions as a folate hydrolase to maintain folate homeostasis.
When we take a closer look into the renal tubule, we have PSMA expressed at the surface of the tubular cells, its job, as I just mentioned, is to maintain folate homeostasis by converting polyglutamate folate to monoglutamate folate form so it can be reabsorbed. After the PSMA radiopharmaceutical injection, it is filtered through the glomerulus and these agents are reabsorbed via two main pathways. The first one, is obviously through the PSMA expression in the proximal tubules. So it binds to the PSMA receptors, it is internalized, degraded, the amino acids are recycled back in the bloodstream and the radionuclide stays stuck in the cells. The second mechanism independently of PSMA is the megalin-cubilin-mediated endocytosis, which is a broad reabsorption pathway in the kidney for all the small molecules and peptides that are circulating and recycled. So again, the PSMA radioligand binds to this complex, it is internalized, degraded, and the radiometal remain stuck in the cells, and the extent of the injury here depends on the radionuclide.
We know that alpha emitters like Actinium-225 cause severe damage in micrometer range. We have beta particles causing moderate damage of millimeters, and Auger electron require intracellular uptake to cause cell-specific damage. Here, I've listed some of the radionuclides and ligands being currently evaluated in clinic, but this presentation will focus on lutetium PSMA because we obviously have the most data here.
So now how do kidneys response to radiation injury? The ADQI Consensus Report defines the kidney injury as an increase in serum creatinine within 48 hours, followed by acute injury up to seven days, acute kidney disease to 90 days, which then progress to chronic kidney disease. This trajectory is not linear and it can follow a lot of different trend. And it has been defined that the RLT injury would follow the yellow trend that we see here, starting as subacute, and then evolving to chronic kidney disease over time, but that would be over a longer period of time than what we see here.
At a cellular level, we know radiation causes direct and indirect DNA damage leading to apoptosis of tubular cells and recruitment of immune cells. We have differentiation between progenitors and injured cells. The kidney can repair itself and move back toward normal function, but the persistent injury drives maladaptive repair with fibrosis, tubular atrophy and progressiveness from loss. And it's a balance between both repairs and the shift to maladaptive repair leads to chronic kidney disease.
At a patient level, this is our proposed clinical timeline. The first six months, no symptom despite the injury. After six months to a year, we can start having symptoms such as proteinuria, hypertension. And after around 18 months or later, we have signs of chronic kidney disease with renal failure. So our main limitation here is that the mCRPC patient don't live long enough to be able to observe those late effects. The VISION Trial overall survival is only 15.3 months, so right here when we're supposed to start to see symptoms. But when we look closely into those 15 months, what can we learn from it?
Well, in the VISION Trial safety analysis, we have no significant difference between the RLT and the control group, appearing up until nearly two and a half years of follow up. When we look closely into the numbers, we do see a slight increase in renal toxicity probability over time, though it also increased in the control arm, which is probably driven just by disease progression. So it feels more like a correlation and not a causation here.
So that's it, that's a critical point so far. We're limited by patient survival, not tissue damage. The injury might be happening, but we just can't see long enough. Other trials are recent and they haven't published long-term follow-up yet, so we're just waiting for those results. Lutetium PSMA has been recently approved for pre-chemo patient earlier in the disease stage, so we'll keep an eye on these results for the next few years.
But in the meantime, what can we expect to see in clinic? What we can observe a rise in eGFR due to compensatory hyperfiltration. It was reported in one in five patients treated with radiation for renal cell carcinoma. And that improvement has also been reported in some lutetium PSMA patient where GFR improved significantly in patients with significantly impaired baseline kidney function, and also a significant improvement of GFR was statistically associated with clinical improvement.
What else? Well, over the long-term, we can expect that eGFR gradually declines. Recent data from multiple centers report consistent pattern. We have a decrease in eGFR starting after six months for both PSMA-617 and PSMA I&T. It seems a tiny bit more important for PSMA I&T here in orange. And another center has reported eGFR decline of 0.15 per month, translating to about 1.8 per year. But again, the number of patients drops over time due to disease progression.
We also have other case report of renal thrombotic microangiopathy following PSMA-RLT, appearing seven to 17 months after the first dose, depending on the agent and the number of cycle. But it's also important to know that TMA reports are not new to lutetium PSMA. It's been reporting with lutetium dotatate and also yttrium-90 therapy. And in the past few years, we've had an increase in publication of TMA reports with a lot of other anticancer agents.
So now we ask the main question, looking at the eGFR draw the TMA reports, is it a causation due to RLT or just a correlation because of the overall patient condition? We'll have a few points to answer that. As I just mentioned, TMA syndromes are a complication of cancer itself and can also occur as a side effect of other anticancer agents. Prostate cancer is the third most common cancer with cancer associated TMA. And we all know that cancer patients have a higher risk of developing acute kidney injury at baseline due to tumor burden, comorbidities, nephrotoxic treatments, and hemodynamic instabilities. So these patients have a very complex medical history. Yes, we observe a lower eGFR after RLT, we saw in the control group. So we have a lot of factors to take into account here related to therapy, related to cancer, related to the patient. Those are too many factors to attribute those reports fully to RLT. But if we take a step back earlier in the treatment course, we would need biomarkers that would be able to detect that injury right after the PSMA or pharmaceutical injection to maybe try to stratify patients.
The blind spot that we currently have is that we rely on serum creatinine and eGFR that are late and sensitive markers reflecting function and not representative of the subacute injury that the kidney may have. So we need to develop new biomarkers and new tools to evaluate early signs of structural injury when we have the subacute injury happening before the function drops.
I wanted to quickly mention some of the biomarkers in discussion today in clinic. We have markers of tubular injuries such as NGAL and KIM-1 and markers of tubular health and regeneration such as EGF. And I also wanted to mention that great preclinical paper looking at radiopharmaceutical kidney injury in mice models, where the traditional biomarkers only capture the injury 28 weeks after the RLT. The new biomarkers detected it only one day after the injection, which is pretty promising.
So as a conclusion, we know lutetium PSMA can injure kidneys through two mechanism, the PSMA expression in the tubules, and the megalin-cubilin-mediated reuptake. We observe a slight long-term decline in kidney function even after an initial compensatory improvement. But the problem is that it remains difficult to attribute this fully to RLT because the patients have a very high disease burden. So our challenge and future work are to use novel tubular biomarkers in patient-specific dosimetry to detect injury earlier and safely expand the use of PSMA-RLT into earlier disease stages. Thank you.