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Welcome and Introduction

Welcome to the continuing pharmacy education activity Empowering the Pharmacist to Improve Clinical and Economic Consequences of Diabetic Kidney Disease. As frontline healthcare professionals, pharmacists frequently see patients with diabetes and those at risk of chronic kidney disease, fulfilling a key role in providing care for patients by helping to screen, identify those at risk, and assist in their referral. As medical experts, pharmacists are often part of the multidisciplinary team to help optimize treatment and cardiorenal outcomes.

Importance of Screening and Early Intervention in Improving Clinical and Economic Consequences of DM, CKD, and ESRD

Dr. Michelle Richardson is a highly respected pharmacist and educator, who serves as the Director of the Outcomes Monitoring Program in the Division of Nephrology at Tufts University School of Medicine, where she is also an Assistant Professor of Medicine. You are invited to join Dr. Richardson as she presents the Importance of Screening and Early Intervention in Improving Clinical and Economic Consequences of Diabetes, Chronic Kidney Disease, and End-Stage Kidney Disease.

Michelle M. Richardson, PharmD, BCPS: I received funding from Dialysis Clinic Incorporated to my employer to direct the DCI outcomes monitoring program. I will not be discussing or referring to any unlabeled or approved uses of drugs, devices, products, protocols, or therapeutic strategies.

In today's presentation, we hope to help you recognize chronic kidney disease as a public health problem that has significant clinical and economic burdens. We're going to describe the causes of the increased prevalence and the associated factors with progression, identify why CKD is under-recognized and also some of the issues that frontline providers have encountered and explain the potential role for community-based targeted screening of at-risk individuals that have the potential to improve both clinical and economical outcomes. And we want to examine how pharmacists can collaborate with primary care physicians to screen and identify at-risk individuals and talk a little bit about the barriers that need to be overcome to make that be successful.

So first, CKD is a public health problem. Over 37 million adults in the United States have CKD, which is about 15% of the population. And although that's a large number, what really makes it striking is that 90% of those individuals do not know that they have kidney disease, and that remains true when you have patients who have severe kidney disease. If you look at the graph on the right, you can see that, over time, and regardless of stage, so stages of kidney disease as the numbers go up the severity increases, and you can see that those with the greatest stages are more aware of their disease. But even people indicated by the blue line, as time has gone over, are more aware of kidney disease, but still a fair amount of them do not know that they have chronic kidney disease.

Chronic kidney disease is more common as people age, and it's also more common in non-Hispanic Black adults more so than non-Hispanic Whites. Although these numbers don't look hugely different as the stages of CKD progress, the disparities become larger. And about 14% of Hispanic adults have chronic kidney disease. And there are many risk factors, the 2 main ones being diabetes and hypertension.

As you can see in this slide, these are for patients with advanced stages of CKD, stages 3 and 4, and diabetes versus hypertension, which are the 2 most common causes of chronic kidney disease. Over time, you can see that those that are diagnosed with diabetes or pre-diabetes, more and more CKD occurs over time. It's less obvious with hypertension, but because hypertension is so prevalent in the population it is a major cause of chronic kidney disease.

This next slide you'll see in each presentation today, but the main point here is that even over time versus the top row, 2006 to 2008, versus the bottom row, 2012 to 2014, that the interventions that we have available to prevent the progression really haven't changed over time. There's a little bit more of blood pressure checks, but there's a little bit less of some of the effective therapies that Dr. Agarwal will be discussing. Patients diagnosed with CKD have a high prevalence of uncontrolled hypertension, which then enhances their risk of CKD progressing.

The reason why those therapies to prevent the progression are so important is that about a third of the patients with chronic kidney disease will progress to kidney failure that requires dialysis treatment or kidney transplantation. These treatments have great burdens on the patients, on the clinical systems, and also economics. And although ultimately, kidney transplantation costs less, most patients in the US are requiring dialysis prior to transplantation because of the lack of organs. In the United States, the burden of CKD is not equally distributed amongst our population, and there are substantial inequalities based on socioeconomic status for a variety of the outcomes of chronic kidney disease.

In addition, chronic kidney disease has significant morbidity. I'm going to use the example of hospitalization here, but there are also other comorbidities that are important. This graph is extracted from a much larger figure in this article that was from the CRIC study, which is the Chronic Renal Insufficiency Cohort. Nearly 4,000 participants were followed up for a median of 9.6 years, and they compared hospitalization rates of these CRIC participants with the nationwide inpatient sample, which is a comparative sample of inpatients in the US. You can see whether it was all-cause mortality, cardiovascular mortality, or non-cardiovascular mortality that the risk of hospitalization increases with decreasing eGFR, which means worsening kidney function. What this study was one of the first to show is that, even with the eGFRs of 45 to less than 60, which we have traditionally thought of as a less severe type of CKD, those patients still had an increased risk of hospitalization.

There's also increased mortality in patients with CKD. Here, you can see this is all-cause mortality by eGFR category. Just first glance on the list you can see that, as kidney function declines, the rate of mortality increases dramatically. The individual lines are the years in which the mortality is reported.

So all of these progression factors, the morbidity and mortality, have an influence on economics, and CKD costs more than 25% of Medicare's annual expenditures. Keep in mind that Medicare only is available for these folks who are 65 and older. That's where these data come from. And if patients with CKD have more than just CKD, so such as diabetes and congestive heart failure, their cost is more than 2 times greater than if they just had CKD alone. You can see on the graph that, over time, these elevated costs have remained over time.

I'm going to just briefly mention the CKD progression factors because these will be discussed in greater detail in subsequent presentations. We know that control of diabetes and blood sugar concentrations are important for maintaining a good kidney function. Albuminuria has a very well-known influence on progression. Monitoring blood pressure and managing it appropriately is important for cardiovascular risk in these patients, which they are at elevated risk for cardiovascular morbidity and mortality. And there are also factors that are based on age, ethnicity, et cetera.

So we've shown that CKD is a public health problem through all of these factors, but the main point that we want to make is that it's under-recognized. And this crazy graph, I'll walk you through it to appreciate how much of the under-recognition is important. So there had been many studies that have shown that around 20%, and there's a range around that, of CKD is unrecognized in at-risk individuals, meaning patients with diabetes or hypertension or other known risk factors. This study was just recently published, and it is over 28 million laboratory values, so this is real-world data. And you can see that these are at-risk patients, so on the left hand side, the blue column is hypertension, which, as we already commented, is one of the risk factors. On the bottom, the maroon color bar is for diabetes. And the purple bar in between is for patients who had both hypertension and diabetes. You can see in the middle bars, the sort of lighter blue or gray, are the people who were actually at risk and appropriately tested. And then below that are the large percentage of patients who are at risk and not tested. What that means is that they did not meet the criteria that our standard and clinical care guidelines of eGFR and the urinary albumin-to-creatinine ratio. These are the 2 tests that are needed to diagnose chronic kidney disease.

You can see that a large percentage of patients have the eGFR value because that's commonly included in the CHEM-7 and so most patients will get that. But you can see that many of the patients who were at risk did not have the proper testing and that actually a fair number of those folks who have significant risks were not identified.

So why might this be? Why is it that there are all these patients at risk? Diabetes and hypertension are well-known comorbidities, but yet we're not recognizing chronic kidney disease in the way that we need to influence its care. So 2 studies have been done that both were qualitative and or mixed-method studies to try to figure out what it is that the challenges are for monitoring patients and screening for CKD in the primary care setting. These studies were done in primary care physicians. So there were several things identified that effect from the patient's point of view, the PCP, and the system view. For patients, the PCPs identified that health literacy is an issue and that having lower health literacy made it very difficult to help patients understand that they had kidney disease and that this was something important that they needed to take care of. They also think that there's a low disease awareness of chronic kidney disease in general and that patients had poor adherence to the treatment recommendations that PCPs would make, all of which makes screening and monitoring very difficult.

From the physicians' aspect, they thought that time was short. They didn't have enough time to speak to these patients in the outpatient setting. As we mentioned earlier, patients with chronic kidney disease have a lot of morbidity and have complex clinical cases that need to be addressed with a lot of time and conversation. They also identified that CKD guidelines were not optimal. They felt they were difficult to follow, that they changed frequently, and they weren't concise. They thought that managing the risk factors for CKD was also difficult in the primary care setting. They had some fear of delivering the diagnosis of chronic kidney disease. And also particularly in non-urban areas, having limited access to nephrology experts was a challenge for them in screening and monitoring CKD. Some also expressed ambiguity in their role. Were they supposed to take primary care of these patients? Were they supposed to refer them? What was their actual role in the care of screening and monitoring CKD patients? And that also that because CKD is silent in nature that patients didn't really believe that they had a diagnosis that could be of concern and that that was more difficult in monitoring CKD.

From the system point of view, inflexible EMRs was a big deal. They couldn't adjust things to what they needed specific to CKD. The limited time and resources on a system level were also identified as challenges, poor reimbursement, and a lack of supportive technology to identify and manage CKD.

They also, in these qualitative research studies, came up with some potential solutions. So to be able to improve CKD care, the primary care physicians wanted useful technology, technology that was supportive and helped identify and manage CKD. Things like electronic prompts, lab decision support, and shared medical records would all help in the efforts to screen and monitor CKD. They wanted concise and easy to use guidelines. They wanted better CKD educational tools. They wanted collaborative health teams that communicated well. And they wanted to have access to nephrologists, which is particularly difficult given the shortage of nephrologists in the United States. And they also wanted healthcare financial reform so that they were more adequately reimbursed for the care that they needed to give to these complex patients. These studies were done prior to some advances that have happened in this area. Dr. St. Peter will be discussing those later on.

So what can pharmacists do to help screen and monitor for CKD in the community to help make up for some of the challenges that the primary care physicians may experience? So there was a study recently published about 4 pharmacies in British Columbia, and they recruited patients with at least 1 CKD risk factor. These were more traditional community pharmacies, but they had point-of-care testing. So through a finger stick, they were able to collect blood and estimate an eGFR, so they did this over a 3-month period, and then the pharmacists gave either comprehensive med reviews or follow-up recommendations, whatever was reported.

During the time of this study, they were able to recruit over 640 patients in these 4 pharmacies, and you can see that the population represents those who you think would be at risk for CKD, people who are older and who had hypertension and diabetes, and also represents the ethnic distributions that you would expect to see in British Columbia. These pharmacists were able to do blood pressure screening in about 98% of these people who were enrolled in the study, they did medication reconciliation in a very large percentage of the patients. However, the follow-up recommendations, particularly with physicians, was one of the lower accomplishments at about 40%. They identified that as a difficult area for them to reach positive effects as much as they had with the other things.

There was also a study recently published. They were semi-structured interviews of pharmacists trying to get at what the challenges for monitoring and screening CKD were in the community. And they identified patient-based factors, pharmacist factors, and also factors that associated with the primary care physician. So for the patients, they also identified lack of understanding and general knowledge about CKD. They acknowledged language barriers as a problem, oppositions to the pharmacist's recommendations, patient's reluctance to take medications, and also the silent nature of CKD as patients don't often experience symptoms until they're in the later stages of CKD.

The pharmacist, just like the primary care physicians, identified time as a challenge. Some pharmacists felt that they didn't have the knowledge of CKD or the renal effects of medications that they felt confident in pursuing CKD screening and monitoring. In a traditional clinical pharmacy, they felt as though workflow would be disrupted. They have a general lack of clinical information in that they don't have access in most cases to the patient's medical records. And then also, staff shortages made these types of activities more challenging.

From the pharmacist perspective, they found that it was difficult to contact PCPs if they had identified someone who may have a diagnosis of CKD based on eGFR, but had problems in reaching that physician. And there was also an extended period of time between the time of contact and response, during which time the patient has probably already left the pharmacy. And that there were oftentimes reluctance on the part of physicians to change a prescription based on a patient's estimated GFR.

They also, in the same study, found the facilitators to make screening for CKD happen. So the patients were really open to being educated and counseled by the pharmacists. They found that, if there were a family member or a close friend involved, that it was much easier to do the screening and monitoring in a community pharmacy. They also thought that, if they had established good relationships with patients, that discussing these types of things was much easier than if they didn't have that relationship. And if patients had knowledge about CKD, that it was much easier to go more in depth and continue the conversations.

From the pharmacist or pharmacy point of view, the thought was that, if there were a consultation area where these conversations could happen, that facilitated the process if the other staff and the pharmacy were well-trained and could do activities related to the dispensing of medications without the pharmacist's direct oversight of every step. If the pharmacist themselves felt that they had a good CKD knowledge base, they were more confident in doing screening and monitoring for CKD. Having access to clinical information made a huge difference. They also identified that software alerts would be very helpful and also documentation software in order to be able to document the results of the testing and then also how the conversation with the patients went and what they had done.

For improving the process with primary care physicians, they thought that a direct phone line would be more helpful to contact the physician with the information while the patient was in the clinic. And they thought that, if the primary care physicians were more appreciative of their communication input, that that would facilitate the process.

So what role overall could pharmacists have in collaborating with PCPs on CKD screening and identification? So pharmacists have unique perspectives. They're likely to see patients more frequently than primary care physicians, they generally have an access to the full medication list so they can identify multiple providers, poly-pharmacy, they can also use medication lists to help identify those patients who are at risk. So for instance, a patient on diabetes medication is very likely to have diabetes. It's also possible for them to know what over-the-counter or complementary therapies that are being taken by the patient, or at least purchased, have that opportunity to discuss those with the patient and the impact that that may have on their kidney disease. They're also able, given if they have the point-of-care technology within the pharmacy, be able to do more frequent check-ins for blood pressure and blood glucose control, and also for adherence to really encourage patients that these things are important and to keep up the good work in maintaining their health.

At the time of selection, they can counsel patients on avoiding certain over-the-counter therapies, especially those that contain NSAIDs, which we know could be problematic in patients with CKD. So it's particularly important with the cough and cold combination medications that have NSAIDs in them. A patient may know to avoid a particular type of NSAID, but when it's mixed in with a cough and cold product, they may not have that same recognition. The pharmacist can also be a great source of knowledge and a source of education for primary care clinicians helping to meet some of those challenges that the primary care physicians identified.

But there are also some challenges for pharmacists. There's the need for point-of-care testing in the pharmacy, the knowledge of how to use it, and any processes and procedures that need to be followed for that. They need to be able to delegate some of the more task-oriented duties to help free up their time to be able to have these conversations with patients and do the testing. They need to obtain and maintain a solid knowledge base about CKD and develop relationships with PCPs and other healthcare providers so that their recommendations are accepted so that they can also learn about the disease and contribute to improving patient's health. There has to be very careful communication, both with patients and healthcare providers. Some of the challenges that Dr. St. Peter will also address are lack of reimbursement. And also the interconnectivity of medical information systems would greatly simplify things so that everyone has the information that they need.

There are also some challenges from the patient point of view. Patients need to be willing to obtain healthcare services in a pharmacy. This is likely to become more and more easy, especially from the results of the pandemic and patients being able to get vaccinated within a pharmacy and have more interactions with pharmacists. The low health literacy of patients with CKD needs to be addressed both in how we communicate with them and also the educational information that is provided to them. And then, patients also need to understand the importance of following up with their physician to have additional testing done or other follow-up that might be needed to help with the diagnosis of CKD and also preventing its progression.

So in summary, CKD is an under-recognized public health problem that has significant clinical and economic consequences and there's ample opportunity for PCPs and pharmacists to collaborate and improve the care for patients with CKD.

Mechanisms of Action of New Agents for CKD in T2DM and Current Guidelines

Dr. Rajiv Agarwal is an internationally recognized leader in the area of clinical and translational research in nephrology who serves on the Board of Directors of Kidney Disease: Improving Global Outcomes. A Professor of Medicine at the Indiana University School of Medicine and a VA clinician, Dr. Agarwal will present Mechanisms of Action of New Agents for Chronic Kidney Disease in Type 2 Diabetes and Current Guidelines.

Rajiv Agarwal, MBBS, MD, MS, FASN, BRCU : Hi, good morning. I'm Dr. Rajiv Agarwal, Professor of Medicine at Indiana University School of Medicine and a staff physician at the VA Medical Center in Indianapolis. I'm going to discuss with you the mechanisms of action of new agents for CKD and type 2 diabetes and the current guidelines.

I have the following relationships to disclose.

Going off what Dr. Michelle Richardson said about diabetes, it's a global scourge. The scourge is growing. The global incidence of diabetes is going to go up from 425 million people to 592 million people.

Now, as you know, diabetes affects the kidneys and the worst complication in kidney is kidney failure, going on dialysis. And it's, again, projected that the number of people who are on dialysis will double. There are about 2.6 million people on renal replacement therapy in 2010 around the world, and that number is more than doubling in 2030. If you examine the areas of the world, it turns out that the areas of the world which have least access to the resources are the most effected, especially Asia. Now, North America is not far behind, and it's a leader in this. It's a disease of both the developed world and the developing world.

The other issue with this disease is cardiovascular disease, and that incidence is increased 2- to 3-fold with diabetes. But once people have kidney disease, that risk is multiplied.

For example, if you look at CKD, which is defined as eGFR of less than 60, and the relationship with cardiovascular death, as eGFR declines, this cardiovascular death increases. But what we often miss is albuminuria. We detect kidney disease often by an impairment in eGFR, but that's kidney failure. We can identify kidney injury at a much earlier stage by simply examining the urine for albumin. That's a very simple test, point-of-care testing device, which measures albumin-to-creatinine ratio. And if that number is more than 30, the patient is said to have albuminuria, and that patient is at high risk of cardiovascular death.

And there's a law of linear relation between every doubling of urine albumin-to-creatinine ratio and the risk of cardiovascular death. So what the slide shows is that there's both a relation between kidney failure and kidney injury, kidney failure being detected by eGFR, and kidney injury detected by urine albumin-to-creatinine ratio. And we can combine these 2 to come up with what is called a KDIGO heat map. And the risk of cardiovascular mortality is increased when patients have increase in albuminuria or impairment of eGFR. And you can see in the red are people who have extreme impairment of eGFR or people who have extreme albuminuria. In these populations, the risk of cardiovascular mortality is quite high.

What we have learned about kidney disease progression is that we can somewhat abrogate it. What we discovered is that there are 3 primary drivers of progression of kidney disease: hemodynamics, glycemia, and inflammation and fibrosis. So we can address hemodynamics by using ACE inhibitors and angiotensin receptor blockers; glycemic control by a variety of therapies, but not just insulin or metformin, but also the newer agents such as SGLT-2 inhibitors and GLP-1 RAs. And then we have an undiagnosed area of inflammation and fibrosis, something that we cannot see directly, but often contributes to progression of kidney disease, which led to the guidelines that we should have a multi-factorial approach.

The very simple things are lifestyle modifications, such as exercising adequately, reducing the sodium intake in the diet, stopping smoking, but also glycemic control, blood pressure control, and lipid management. The lipid management is particularly important because atherosclerotic events are quite common in this population. And it has been shown that use of statin-based therapies can reduce the incidence of cardiovascular events in such patients. But as we have now seen is that we have RAS blockade and SGLT-2 inhibitors, and some patients might also need anti-platelet therapies.

Taking a lead from the history of nephrology, in 2001, nearly 20 years ago, we did 2 landmark trials. These were published in the same issue of the New England Journal, RENAAL and IDNT, they used ARB and they showed that they could reduce the rate of progression of kidney failure in people with type 2 diabetes and chronic kidney disease. But what we also recognized was that, despite using these drugs, people continued to progress to kidney failure, what is highlighted on the slide as residual risk.

Now, many years later, which 2019, we discovered that the use of the drug canagliflozin, an SGLT-2 inhibitor, can reduce the progression on top of optimal use of ACE and ARBs. But despite this victory, the patients on canagliflozin continued to progress to kidney failure.

So what was the missing link? It seemed like it was inflammation and fibrosis. And could it be that it's the mineralocorticoid receptor over-activation that leads to this inflammation and fibrosis. This is not anything new.

Hans Selye, who was a Viennese physician and migrated first to US and then to Canada, showed for the very first time that the animals who were treated with desoxycorticosterone acetate, which is similar to aldosterone and sodium chloride, could actually have very high blood pressure, very impaired cardiac function, a stiffening of the aorta, and cardiac and kidney fibrosis.

In other words, he recognized that the use of the MRAs can have hemodynamic and profibrotic effects in 1943. So the logical conclusion was that we could use drugs that could block the mineralocorticoid receptor, the steroidal MRAs, for example, spironolactone and eplerenone, and we could abrogate the progression of kidney disease and cardiovascular disease.

So we did that in the RALES's trial. This was not a population with kidney disease, but these are patients with heart failure with a low ejection fraction who are treated with spironolactone. Unfortunately, these patients became hyperkalemic. Eplerenone was tried in patients with type 2 diabetes and microalbuminuria. Unfortunately, these patients became hyperkalemic. And eplerenone package insert quite clearly says that it's contraindicated in patients with type 2 diabetes and microalbuminuria. In fact, if you have hypertension and creatinine clearance is less than 50, eplerenone is contradicted, according to the package insert. In other words, you could use eplerenone in these patients, but you risk hyperkalemia. Similarly, when patients were given spironolactone after the publication of the RALES trial, these patients often had a higher potassium and a lower eGFR, and these patients got hyperkalemic. So these drugs are sort of dangerous in this population, and this has been shown quite repeatedly in small trials that have been done in nephrology with spironolactone and eplerenone.

This is a meta-analysis published in 2009, has been updated a few times now, but they all show the same thing, that, yes, you can use spironolactone and eplerenone and it will reduce proteinuria and the blood pressure. However, the risk of hyperkalemia will go up 3-fold, and 2-fold approximately with eplerenone. And there's really not much improvement in eGFR. The numbers are small. Each study has a limited number of patients, and there's no net benefit to the patient in terms of the march towards dialysis.

So the question becomes, can we really block the mineralocorticoid receptor, yet not cause hyperkalemia?

So there was a very nice proof of concept study that was done in animals. And the investigators in Australia in the lab of Greg Tesch, PhD, knocked out the mineralocorticoid receptor, either in the myeloid cells or in the podocytes. And they found that it's not the podocyte MR that is important, but the myeloid cells.

So if you knocked out the mineralocorticoid receptor in the myeloid cells, it produced less inflammation and less kidney injury than when you knocked out the podocyte MR. It turns out that, when you knock out the mineralocorticoid receptor selectively in the myeloid cell, you don't produce hyperkalemia and that's really the advantage of it. And so it's a proof of concept that, yes, you can knock out the MR, you can have the benefit in the kidney and in the heart, yet you can spare the potassium.

So once we had this knowledge, there was a race to develop drugs that could block the MR without having the steroidal structure of the eplerenone and spironolactone, and it was felt that if they became nonsteroidal MRAs, that it could spare the potassium, yet produce a lack of inflammation and fibrosis in the predisposed patients.

Eli Lilly developed a drug, Pfizer developed a drug, and both pretty much abandoned their programs.

But there are 2 drugs that were approved, and they are approved in Japan. One is called apararenone, which is by Mitsubishi Tanabe, and Daiichi Sankyo has a esaxerenone, which is approved in Japan for treatment of hypertension. But this was outside the United States. Finerenone was developed in the United States and in Europe. And basically, it was developed in first phase 1 and then phase 2 and phase 3 trials. And I'm going to discuss a little bit more about the development of finerenone.

So here are some preclinical studies. First of all, what the investigators show here is that they selected out a dose of finerenone that produced the same amount of sodium loss in the urine of rodents. And they discovered that 10 milligrams of finerenone is approximately equivalent to 100 milligrams of eplerenone.

So when they treated these animals with the equinatriuretic doses of these 2 drugs, what they found was finerenone, despite producing the same degree of natriuresis, actually lowered proteinuria more, and it improved glomerulopathy and tubular degeneration, and improved vasculopathy. So what they were showing was that it was helping both the structural damage and the histological morphology in the kidney.

The same thing was true in the heart. Compared to eplerenone, finerenone produced less myocardial fibrosis and better cardiac function and less inflammation. And this was in isoproterenol-induced cardiac fibrosis in mice. So they were pretty much showing that it was protecting both the heart and the kidneys, and there was not much of a signal for hyperkalemia. And that led to subsequent phase 2 studies and phase 3 studies.

So FIDELIO-DKD was basically hypothesized that, if you used the drug finerenone and blocked the MR, it could inhibit the inflammation and fibrosis in the heart and the kidneys, and thereby improve both the cardiac outcomes and the kidney outcomes in patients with type 2 diabetes and chronic kidney disease.

We took a wide range of patients who had an eGFR anywhere between 25 to 75 and had an albuminuria anywhere between 30 milligrams per gram protein, all the way to 5,000. We excluded people who had HFrEF, because in those people, spironolactone might be indicated, and we didn't want to deny these people spironolactone if it was so indicated. We also excluded people with severe uncontrolled hypertension. And because we recognized that this drug could cause potential hyperkalemia, we randomized only those patients who both, at baseline and screening, had a serum potassium of 4.8 or less. So that was really important. And we optimized the dose of ACE inhibitor or ARB for 4 to 12 weeks. So we only took those patients who failed optimization and randomized them into the trial.

So as a result, because of such a strict run-in and screening, we started with 13,911 patients and we ended up with 5,734 patients randomized to either finerenone or placebo. Finerenone was dosed in 10 milligram per day if eGFR was less than 60. But if the potassium was fine, we titrated it up to 20. And finerenone was given at a dose of 20 milligrams once a day if eGFR was more than 60. Median follow-up was 2.6 years. The primary endpoint was a kidney composite and defined as eGFR decline of 40% or more from baseline, or kidney failure, like dialysis or transplantation or death from kidney causes. There's a cardiovascular composite, which is a 4-component cardiovascular MACE outcome, which is myocardial infarction, stroke, hospitalization for heart failure, or cardiovascular death. And then we had 4 hierarchical outcomes, which, first of all, was death from any cause, then hospitalization. And then we had change in urine albumin-to-creatinine ratio and the second kidney composite.

The trial characteristics. Typical age was 66 years. Blood pressure is well controlled. A1C was 7.7. All the patients were on ACE inhibitors or ARBs. In fact, we even allowed SGLT-2 inhibitors, about 4.5% of people, and 7% were on GLP-1 RAs. Nearly all the patients were on glucose lowering therapies. It was a fairly advanced population.

Mean eGFR was 44, so less than 45 eGFR in more than half the patients. And UACR was more than 300 or macro-albuminuria in 87.5% of the people. So we have a population of fairly advanced kidney disease.

We found a nice reduction in albuminuria, 31% within 4 months, and that reduction stayed reduced for the duration of the trial.

Blood pressure went down about 3 millimeters or so, and it was reduced most of the trial. And A1C, there was no between-group difference in A1C, because this is not an anti-diabetic drug.

The primary endpoint was met. We had success in reducing kidney failure outcome in this trial, favoring finerenone.

And the components of the endpoint all favored finerenone, including dialysis or sustained decline in eGFR, et cetera.

The secondary endpoint in this trial was cardiovascular, and that was also met. There was a 14% relative risk reduction for cardiovascular outcome.

And the hierarchical endpoint analysis showed that we had reduced that, but only by about 10%. That was not statistically significant. So everything below that is exploratory. In fact, we have a very nice reduction in UACR, about 31%. The secondary composite kidney endpoint is important to know. That's the endpoint that typically people use in clinical trials, which is the doubling of serum creatinine endpoint. And that doubling of creatinine is basically a 57% reduction in eGFR. And instead of an 18% effect, you now have a 24% relative risk reduction. So nearly 50% larger effect if you use the more traditional endpoint of doubling of serum creatinine, death, dialysis, or transplantation.

So we have now calculated a number needed to treat to prevent 1 kidney failure outcome, which is about 29, and cardiovascular outcome, which is 42. And this is happening despite very little reduction in blood pressure and there's consistency of effects on the primary endpoint and in key subgroups.

What about the side effects? Well, the adverse effects leading to treatment discontinuation was slightly higher in finerenone group. And the majority of the treatment discontinuations occurred because of hyperkalemia or increase in blood potassium. In fact, 64 events in the finerenone group versus 25 events in the placebo group. And you can see the trial is more than 5,000 patients, so relatively small number of people who permanently discontinued the medications because of hyperkalemia.

And we look at it in a more granular way, we find that any treatment-emergent AE for hyperkalemia was approximately twice as much in the finerenone group compared to placebo. We look at it another way, you basically see that 82% of the patients who got finerenone never had any hyperkalemia, even in an advanced population. Nobody died because of hyperkalemia. There was only 1 patient who received dialysis because of hyperkalemia, and that patient was in the placebo group. And the number of patients who had permanent discontinuation because of hyperkalemia was 2.3% in the finerenone group, 0.9% in the placebo group. So if you do the math here, you will have to write 71 prescriptions to 71 patients before 1 of them goes off the drug permanently. So it's a fairly different drug when you look at it in terms of other treatments.

There is a small increase in serum potassium, about a 0.23 millimoles at month 4.

So here's the summary of the trial. It works, but there's a small expense of hyperkalemia.

Well, you might wonder, how does it compare to other therapies where we have tried combined RAAS blockade? We have, of course, been trying combining ACE inhibitor to ARBs, and we have tried the renin inhibitor aliskiren with ARB in the ALTITUDE trial. And turns out that, in both these trials, there was hyperkalemia seen, and there was no efficacy in either one of these trials. FIDELIO used a combined blockade. And we find that, yes, it has efficacy, and it's also got a small incidence of hyperkalemia, much less than what was seen in the prior trials.

We haven't done any head-to-head comparison with spironolactone, aside from a small phase 2 trial, which was called the ARTS. And there, we find that spironolactone had more hyperkalemia compared to finerenone. But perhaps a better analogy can be drawn from considering the AMBER trial that was done in patients with resistant hypertension and eGFR between 25 and 45. Everybody in this trial got spironolactone, but half the patients got placebo, half the patients got patiromer, which is a drug that reduces potassium by binding potassium in the gut. What we found was that 23% of the patients on placebo went off the spironolactone within 12 weeks. Even when they got patiromer, 6.8% of the patients went off spironolactone because of hyperkalemia mostly. And you have a very small incidence of patients who are going off finerenone, with a median follow-up of 2.6 years, not weeks, but 2.6 years. So somewhat very different profiles of the drugs.

In part, it is because finerenone has got a very short half-life, 2 to 3 hours, has got no active metabolites. And as you know, spironolactone is a pro-drug. It's metabolized to canrenone and 7α-thiomethylspironolactone. And 7α-thiomethylspironolactone has got a half-life of 168 hours, which is nearly a week. So in fact, what we found was that most of the patients had metabolites of spironolactone 2 weeks after stopping the drug. And 2 weeks after stopping spironolactone, we still had more than half the blood pressure effect remaining in these patients. So spironolactone is something which is extremely long acting, much likely to cause hyperkalemia, in part because of its very long pharmacokinetic profile compared to finerenone, which is short and has no active metabolites. So overall, we find that it's got both a kidney benefit and cardiovascular benefit.

Now, the story is not over. We actually have a FIGARO trial, which is looking at cardiovascular morbidity and mortality in a population which has an earlier stage of diabetic kidney disease; 62% of these patients have an eGFR of more than 60, and nearly half of them have microalbuminuria. So this is a much earlier stage of kidney disease, and we're looking at the cardiovascular endpoint in the FIGARO trial.

In summary, we find that we have to have a multi-factorial approach, which starts with screening for hypertension and kidney disease in these patients. Nonsteroidal MRA can be quite useful, and these drugs have the potential to protect both the kidney and the heart across the whole spectrum of people with diabetes and kidney disease. A multifactorial approach is really needed. We have to restrict dietary salt, the blood pressure control, glycemic control, statin-based. And then we have to ask ourselves, why is the patient not on triple-drug therapy, which includes an ACE inhibitor or an ARB, an SGLT-2 inhibitor, and now finerenone.

Finerenone, as you know, was approved by the FDA on July 9th, 2021, for use in patients with chronic kidney disease associated with type 2 diabetes, to protect the kidneys and the heart, if eGFR is 25 or more and potassium is 5 or less. But people now often ask, "Didn't you exclude patients with less than 4.8 in the trial? These are patients, they had a 4.8 milligrams potassium or more were excluded. How come you got an indication for less than 5?" And the answer is very simple. In this trial, we had a baseline and a screening period, during which the potassium had to be less than 4.8. But after the baseline, there could be 2 weeks lapsed before the patient got randomized. And there were many patients, several hundred patients, who had a potassium of sometimes more than 5 at the time of randomization. So if you look at the totality of the data, 5 seems to be a good number. And when you treat these patients, it's important to keep monitoring the potassium, the blood pressure, the sodium, the volume status, because that's just good clinical practice in these individuals.

Throughout her career in pharmacy, Dr. Wendy St. Peter has been focused on improving medication management and drug safety in patients with chronic kidney disease, conducting pharmacoepidemiology and health economic and outcomes research. A Board Member of the Kidney Health Initiative, Dr. St. Peter will address the Pharmacist's Role in Guideline-Directed Treatment and Other Strategies to Optimize Outcomes in Chronic Kidney Disease.

Wendy L. St. Peter, PharmD, FCCP, FASN, FNKF: Hello. I'm delighted to be here to talk about this really important topic.

Here are my disclosures.

Today, I want to talk about utilizing some key treatments and treatment guidelines for hypertension, diabetes, and lipid management in patients with chronic kidney disease to improve both kidney and cardiovascular health. I also want to take the opportunity to talk about new opportunities for pharmacists to integrate into the care team for patients with kidney diseases.

Dr. Richardson has already presented this slide, but I wanted to talk about it now in the context specifically of blood pressure. How are we doing in CKD blood pressure management? Well, this slide shows in more recent national data that less than 50% of patients are controlled to a blood pressure less than 130/80, and that's something we need to really think about, because in the context of new guidelines that we have, which I'll be introducing in a moment, we're failing even at 130/80, and we're going to have some more-stringent guidelines that have come into effect that is going to pull us even further away from our blood pressure management goals.

So today we have the KDIGO 2021 Clinical Practice Guideline for management of blood pressure and chronic kidney disease.

And what did this guideline say? Well, there are 2 key recommendations. One, that the target blood pressure recommendation changed from less than 130/80 to a target systolic blood pressure less than 120 in patients with chronic kidney disease. And importantly, and I'll be talking about this more later on in the presentation, is that target is contingent on using proper blood pressure management techniques.

So how did we get to this new blood pressure goal? Well, it had all to do with the SPRINT, the Systolic Blood Pressure Intervention Trial. So our KDIGO target blood pressure was highly influenced by this 1 clinical trial. I just wanted to go a little bit into the specifics of this trial. They enrolled almost 10,000 patients at high risk for cardiovascular disease, which included those who were greater than 50 years old with cardiovascular disease, those with chronic kidney disease, those that were simply over 75, or had a Framingham Risk Score for CVD that was greater than 15%. Importantly, and I'll talk about this later, they excluded those with diabetes. And of course, diabetes is the largest cause of end-stage kidney disease in the US. But in this trial, over 28% of the patients had CKD with an eGFR less than 60, which makes this clinical trial the largest blood pressure trial for those patients with CKD. The treatment arms were intensive blood pressure control where targeted systolic blood pressure of less than 120 was used. And they also had a standard blood pressure control group where the target was a systolic blood pressure less than 140.

The trial ended early because, as you can see from this insert on the slide, that intensive treatment, which is the orange line, versus standard treatment, which is the blue line, had a lower incidence of a combined endpoint. That is a 25% reduction in myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. The trial was ended early because they reached this statistically significant endpoint before the trial was slated to end. So after about 3.6 years of follow-up, the trial ended.

That really influenced the KDIGO blood pressure guidelines, which suggest that adults with high blood pressure and chronic kidney disease be treated with a systolic blood pressure of less than 120 when tolerated using standardized office blood pressure measurement. So this lower systolic blood pressure, this lower goal, is based on those important primary, that combined event that we're focused on cardiovascular and mortality benefits and not kidney-related benefits, but this is important because the single largest cause of death in patients with chronic kidney disease is cardiovascular events. So it's important to understand that these new guidelines, KDIGO guidelines are based mainly on the SPRINT trial. There really are no new randomized control data beyond the SPRINT trial.

And it's really important to understand that, although they've said these guidelines for less than 120 systolic blood pressure for the majority of CKD patients, that there are some patients that weren't studied in this trial, or they didn't have a lot of patients. So, the evidence for that is not as strong. And that of course, is in patients with diabetes. They didn't include diabetes patients in this trial, which is too bad. And you just need to know that the ADA still uses a goal blood pressure of less than 130/80 in patients with diabetes at high cardiovascular risk, which would include chronic kidney disease patients.

There weren't a lot of patients with advanced CKD, and of course extreme ages. So the average age in this study was around 68. So there weren't a lot of younger patients and there weren't a lot of really old patients, and they didn't include patients with low diastolic blood pressure. So just keep these caveats in mind, although that's the goal blood pressure that KDIGO's advocating, that there's not as much evidence in these populations. And so some individualization, of course is merited.

Some other caveats to this trial are that the average systolic blood pressure that was actually achieved was not below 120. It was actually 121.5 in the intensive treatment group. And importantly, when they took a look at the blood pressures that were documented in the trial and then compared it to electronic health records data from those same patients from their office visits, that the EHR blood pressure was 7.3 mm of mercury higher. So that is something we all have to think about as clinicians. What are the implications? If we are going to safely implement this target blood pressure of less than 120, we all need to consistently use guideline protocol approaches to measuring office blood pressure.

And so the KDIGO guidelines, and you can find the standardized office blood pressure measurements and other recommendations as well. But I think when you look at this long list of things that we all as clinicians need to think about when taking a blood pressure in any patient, you need to be aware of these. So it's not only things that you do in the office, but you need to properly prepare your patients to come in to have their blood pressure taken. The patients should avoid caffeine, exercise, smoking for at least 30 minutes before their measurement. They should empty their bladder. They shouldn't do what I do, run up to my primary care office up the stairs and then have the blood pressure taken right away. So you want to sit them down, have them rest. It's oftentimes the nurse aide will talk to the patient, put the blood pressure cuff on.

And oftentimes now what I'm seeing in my own primary care office, they put the automatic blood pressure cuff on, they talk to you and leave you alone. And then they leave for the next 10 minutes, and then the blood pressure automatically goes off and takes 3 blood pressure recordings. So, that's another part of this, is that 1 blood pressure recording is not adequate. You should take at least 2, if not 3, 3 is best, and average those recordings. And in fact, when you're monitoring patient's blood pressure over time, they advocate not only the average of 1 single office visit, but average over multiple office visits so you can really have a good sense of what the average trend in blood pressures are over time.

Of course, Dr. Richardson talked about ACE inhibitors or ARBs and so did Dr. Agarwal. They are still the mainstay of our treatment in terms of reduction in chronic kidney disease progression. They're generic, they're cheap. And as you can tell by this slide, that we only have about a third of patients in national data that have the indication, the chronic kidney disease patient have the indication, to have an ACE inhibitor or ARB that are actually on these agents, just one-third. That's a wake-up call for pharmacists. Something that we can do about in terms of screening for these patients, and if we find out that they have CKD, advocate for ACE inhibitor and ARB use.

Similar to the KDIGO 2012 guidelines, the new 2021 guidelines suggest using these agents. And I just want to point out on this slide these 2 recommendations are focused on patients without diabetes. So KDIGO recommends starting RAS inhibitors for people with high blood pressure, chronic kidney disease, and severely increased albuminuria. That means patients that have albumin-to-creatinine ratios that are greater than 300.

You notice for the next recommendation, for 3.2.2, they soften the language. They suggest starting RAS inhibitors in the same group of patients with moderately increased, and that means between 30 to 300 urinary albumin-to-creatinine ratio. And the reason is that there's not as much evidence for that population. The trials that were evaluating ACE inhibitors and ARBs and CKD patients simply weren't long enough, you could see the trends in positive directions, but again, the trial's not long enough to demonstrate conclusively like they are with patients with severely increased albuminuria.

Now, this recommendation is specifically for patients with diabetes, so they recommend starting RAS inhibitors in patients with high blood pressure, chronic kidney disease, and moderately to severely increased albuminuria. So for this group of patients, even patients that have albumins down to 30, so from 30 to greater than 30 should be started on a RAS inhibitor. So the bottom line, when you're evaluating patients with chronic kidney disease, patients that have chronic kidney disease, high blood pressure, and urine albumin-to-creatinine ratios that are greater than 30 should be considered for ACE inhibitor or ARB therapy, unless there's a contraindication, such as angioedema or anaphylactic reaction to these agents. Hyperkalemia is not a contraindication, because we do have drugs now and other measures that we can use to try to manage hyperkalemia. Also, a drop in an eGFR less than 30% or an increase in serum creatinine greater than 30% after initiation and dose increases are not a contraindication. So hyperkalemia and the drop in eGFR, which we expect because these drugs reduce glomerular pressure. That's why they are effective in terms of long-term use in reducing kidney progression. So those aren't contraindications.

And some data that reinforce this are data that are taken from a health system. So for EMR data, they had about 4,000 patients. And they looked at patients that had an eGFR that dropped below 30 while the patients were on ACE inhibitor and ARB therapy. And then they looked at the patients that continued ACE and ARB therapy, and those that discontinued, and you can see the patients that have continued it are in the blue line. And that meant the ACE inhibitor and ARB treatment continuation group had a higher survival than the patients that discontinued the ACE inhibitor and ARBs. They also did a secondary analysis that looked at patients who had initiated ACE inhibitors, but their eGFR decreased greater than or equal to 40% within a year of initiation, then looked at that group that continued and saw the same thing. So mortality was less in patients that continued the ACE inhibitor and ARB treatment.

They also saw those same kinds of trends for MACE events. There was another study using Swedish registry data that really validated the results of the previous study that showed that RAS inhibitor discontinuation was associated with increased mortality, increased MACE outcomes, but also they found interestingly a decrease in patients going to kidney replacement therapy. But it makes total sense, because when you remove the drugs, you do see the eGFR go up. Remember these drugs reduce glomerular pressure, which reduces eGFR. So when you take these drugs off, you will see a rise in the patient's eGFR, which then allowed the nephrologists to determine that maybe they didn't need to go on dialysis quite so quickly.

So as pharmacists, we do need to have and consider the benefits of these drugs for both delaying CKD progression, also decreasing mortality and MACE outcomes, but we also have to directly address those barriers and risks, that fear and uncertainty, when patients develop hyperkalemia, they have a decline in their kidney function, which oftentimes, primary care physicians, pharmacists, nephrologists are fearful that the patient has acute kidney injury.

Some of the solutions that we can employ in these patients are using the sick day rule. This is where you have when patients are sick, they're not eating, not drinking, they may be throwing up, dehydrated, those produce glomerular pressure hemodynamic effects. On top of an ACE inhibitor, you can get even a more severe dip in their kidney function. It is controversial though, because there are some people that have noticed by using these sick day rules that patients don't get restarted on their ACE inhibitors and ARBs after they are no longer sick, and that's problematic. So my advice is that, in patients that are sick for a day or 2, wouldn't necessarily discontinue their ACE inhibitor ARBs, but somebody with prolonged sickness and prolonged inability to take in food or drink, then it makes sense to discontinue. But it's really important to make sure they get re-instituted on those agents once their illness is past.

Some other things that you just have to think about, those other drugs that also affect the glomerulus, like loop diuretics, which of course reduce blood flow into the kidney, reduce glomerular pressure, SGLT-2 inhibitors, don't start those things at the same time. We want to put 1 drug on board, evaluate the effect on kidney function, that eGFR, and then start a second drug. We also can use potassium binders to maintain ACE inhibitor and ARB use. Dose reduction is really a step, if eGFR, for instance goes down more than is recommended. But having said that, we still have a lot of questions about how far and how low we can allow that eGFR to go. We've got a randomized control study underway, the STOP-ACE trial, that hopefully will give us some of that information.

Dr. Agarwal talked about potassium binder use, but I just wanted to touch on it again. We've got 2 agents, patiromer and sodium zirconium cyclosilicate. Both of these drugs have been evaluated specifically in patient populations that are on ACE inhibitors and ARBs for their ability to reduce potassium and keep the potassium in a safe range. You can see that in the OPAL-HK trial, patients started out with an average potassium about 5.6. And you can say within a week or so, and over time, the potassium was reduced into a safe range in both patients that had higher and a bit lower potassiums to begin with. Same thing, you can see with the sodium zirconium cyclosilicate, the HARMONIZE trial. Within a short period of time, you could see the reduction and a sustained reduction over time in patients that were given it in this trial over 1 year.

So an approach to patients at risk for hyperkalemia is just, first, recognizing as a pharmacist, as the patient's eGFR goes down, you're going to have an increased risk of hyperkalemia because the kidneys are the main way that potassium is cleared. Approaches, thinking about, what other drugs may be causing hyperkalemia? Is the patient taking over the counter nonsteroidals? Is that necessary? Nonsteroidals reduce blood flow to kidney and reduce glomerular filtration and pressure. So that would be one that you would want to discontinue if possible. Getting patients to a dietician and working to have them reduce the potassium in the diet is another part of the solution.

Our potassium binders, we talked about, I just wanted to touch on a couple more things. Shouldn't be using Kayexalate anymore. There's very limited evidence-based, there's an inconsistent effect with that drug. And of course there's a rare, but it has been fatal GI impaction occurs with Kayexalate. Patiromer may be a better solution for chronic therapy in chronic kidney disease patients, mainly because this drug does not contain any sodium, and of course, sodium increases water retention, which is an issue, especially in stage 4 or 5 CKD patients.

Sodium zirconium cyclosilicate is better for acute kalemia with the doses that were evaluated in the study. It has a much faster onset of action and, in fact, has been used in EDs now for acute hyperkalemia, along with other management strategies. Also, sodium zirconium cyclosilicate has less problems with hypomagnesemia as compared with patiromer. Has a little bit more GI effects and also consider the sodium load. It has about 500 milligrams of sodium per every 5 gram dose. One of the strategies that can be used is increasing your diuretic dose. Oftentimes patients in stage 4 or 5 CKD are going to be on diuretics, so simply increasing the dose of diuretics may both deal with the sodium load from SZC but also hyperkalemia.

This is the KDIGO recommendations for monitoring ACE inhibitors or ARBs, and the first thing I want to just put your attention to is the bottom of the slide, emphasizing that either reducing the dose or stopping ACE inhibitors or ARBs are things that should be used as last resorts, but how do we monitor these agents? And as you initiate or increase the dose of an ACE and ARB, you should monitor the serum creatinine and potassium within 2 to 4 weeks. They work very quickly on glomerular hemodynamics, so you can see the effects within 2 weeks. So after starting or changing dose that needs to be done.

In patients that remain normokalemic, as long as you don't see more than a 30% increase in serum creatinine, you can go ahead and increase the dose of ACE and ARBs and titrate that drug up to the maximally tolerated dose. In patients that become hyperkalemic, we've already talked about some of the strategies. So we talked about those, and in those that have an increase in serum creatinine greater than 30% after initiation or dose increase, think about, are there any causes for acute kidney injury? Should look for correcting volume depletion, concomitant medications that can cause volume depletion like diuretics and nonsteroidals, and then make changes in those to try to keep that ACE inhibitor and ARB on board. If you can't find a reason and the serum creatinine goes up greater than 30%, then the whole idea would be to step back to the next lower dose, but keep the patient on the drug.

I just wanted to touch on glycemic monitoring and targets in chronic kidney disease patients with diabetes. The KDIGO guideline is really embracing an individualized goal for hemoglobin A1C. And what you can see is that, depending on severity of symptoms and things and co-morbidities and length of lifespan and stuff, for instance, we should be treating patients that have higher levels of kidney function, have long life expectancy, few comorbidities, absent or minor macrovascular complications, those cardiovascular complications should be treating more aggressively. So down below a hemoglobin A1C, low 7, even down to less than 6.5. And those that have more co-morbidities, have a shorter lifespan, closer to dialysis. Those that also have hypoglycemia unawareness. They don't have resources if they become hypoglycemic. Those, we should loosen up a little bit on that hemoglobin A1C target.

I also wanted to talk about lipid management and chronic kidney disease. Almost everybody that has chronic kidney disease that's not on dialysis should be on a statin, because dyslipidemia is common in CKD. We do know that, in our patients with chronic kidney disease, the low density lipoprotein cholesterol does not reliably discriminate between those at high or low risk of cardiovascular events. So their advice is to monitor and do their lipid profile when CKD is diagnosed and then no need to follow-up for the majority of patients. In CKD patients that are greater than 50 years old that have an eGFR less than 60, we should start a statin or a statin with ezetimibe. In patients with eGFRs greater than 60, start a statin. In adult kidney transplant patients, start a statin. But in dialysis patients that aren't already on a statin when they've reached dialysis should not be initiated. We have 2 clinical trials that have shown clearly that putting dialysis patients on statins are not an effective way to reduce cardiovascular risk. So if somebody is on a statin, they're CKD, they go to dialysis, you can continue that statin, but do not start a statin in a patient that's on dialysis.

Treat to target or goal is not recommended. And just like with other patients, we're treating them with doses, we're not treating down to a certain level of LDL cholesterol, but it's really important to understand that patients with chronic kidney disease do have more side effects. And so you can see on the right hand side the doses that are suggested in patients with CKD, and these fall more into the moderate and low intensity ranges, just because these patients do have more side effects.

Now, as pharmacists, we haven't been involved greatly in the care of patients with chronic kidney disease, but I'm telling you that needs to change, and there's some impetus for change. Kidney health became a national priority in July, 2019, when our President signed an executive order to advance American kidney health. And there were some bold goals that were outlined for this initiative: decreasing the number of Americans developing kidney failure by 25% by 2030, aiming for 80% of new kidney failure patients in 2025 to receive either home dialysis or transplant, which gives those patients with end-stage kidney disease a better quality-of-life.

So the Centers for Medicare and Medicaid Services, CMS, developed new payment models. These new kidney care payment models are value-based payment arrangements that incentivize clinicians to provide high value services that are focused not just on seeing the patient, that fee-for-service mindset, but for quality outcomes and cost containment. So how are they going to do that? They want to shift the monies that are being used in end-stage kidney disease and transplant patients, basically to invest in earlier intervention in CKD stage 4 and 5. They want to reward increased utilization of home dialysis, so making patients more active in their own self-care, higher quality-of-life, being able to do your dialysis at home if you reach end-stage kidney disease. And lastly, there's significant bonuses and rewards for getting patients to transplantation and keeping the kidney healthy and the patient healthy for 3 years post-transplant.

So why and how does this open up opportunities for pharmacists? Well, we know that pharmacists are one of those frontline workers that see patients more than even primary care physicians. Dr. Richardson pointed out that point-of-care testing for serum creatinine and urine albumin-to-creatinine ratio can be done and has been done in community pharmacies. That information is shared with the patient's primary care physician, getting them recognized that they have CKD is step 1 to getting patients into the care they need. Many pharmacists, especially independent pharmacists and those that are advocating for advanced services in their pharmacies are doing blood pressure, lipid control, diabetes control already, and working with patients on medication adherence. And this is what it's going to take for reducing progression of kidney disease: getting the patients on the right medication, monitoring them, and dealing with the diabetes and blood pressure control in particular.

We have ambulatory care pharmacists that are out there embedded in primary care clinics or working with specialty clinics, geriatrics. We've got those in transplant, of course, and we've got pharmacists working even in some nephrology clinics. These new kidney care models that really focus in on nephrologists, and then there are other models that focus in on nephrologists along with other care partners with transplant centers and dialysis centers, have certain performance-based components that really require optimal medication management. Two of them are the patient activation measure. So one of the questions on that particular scoring system has to do with medication knowledge. So pharmacists working with patients to increase medication adherence and activation in their own self-care will improve that measure. Also, depression remission. A lot of patients with CKD have depression, and we know that depressed patients don't follow up on their therapy, nor their medications oftentimes. So that's really key.

There's a new measure that will be eventually coming into place and that is a CKD progression measure. That's going to be perfect for pharmacists. We've got a shortage of nephrologists. We have more pharmacists out there that want and highly desire clinical positions to work with patients, that CKD progression, getting the right medications into the right hands and monitoring those patients for safety and efficacy are key. And some of the specific pieces of these payment models will give separate payment on top of the value-based bundled payments that practices will get for their panels of patients. So they have a kidney disease education, as well as post discharge home visits, enhanced benefits that can be used outside of that value-based capitated payment to provide medication management services.

So understanding that and understanding this is an opportunity, a number of pharmacists got together about a year and a half ago and developed an initiative to advance kidney health through optimal medication management. I happen to be one of the leaders of this initiative, along with one of my colleagues, Rebecca Maxson, from Auburn University.

Our vision with our initiative, and right now our initiative not only includes pharmacists, but nephrologists, pharmacy organizations, patient advocates and their advocacy groups, policy experts, our vision is that every person with kidney disease receives optimal medication management through team-based care, including a pharmacist, to ensure medications are safe, effective, and convenient for the patient to use. And our mission is to engage pharmacists and other key stakeholders to develop partnerships for optimal medication management. We have engaged the Renal Physicians Association, many of our pharmacy organizations, big patient advocacy groups, like the American Association of Kidney Patients, and others to help us, along with working with CMS themselves, to help pharmacists get incorporated into the care of these patients.

We've got 4 main strategic initiatives. I think Dr. Richardson commented in her presentation that many pharmacists don't quite feel comfortable about how to manage CKD patients, and we're addressing that. We're in the process of developing pharmacy practice standards for optimal medication management, like our Canadian colleagues have, and formulating education standards curriculum and training for more consistent training for pharmacists and patients with kidney diseases. As I noted, we have a big engagement tactic to work with all the key stakeholders, all the team members in CKD to drive this optimal medication management practice into not only new value-based kidney care models, but into health systems and even wrap around kidney care companies that are providing these kinds of services. And we're going to do that through development of a learning and action collaborative that helps with mentoring, coaching a pharmacist and their teams to help incorporate using scientific methods, implementation procedures, to incorporate pharmacists into these care teams.

I just want to just show you, again, who the initiative leaders are and who are the leaders of each one of these work groups. We have over 65 people that are involved with multiple organizations that they represent in this initiative.

I just want to conclude today by just noting, again, that these CKD patients have complex medication therapy management issues, and pharmacists need to be involved, with nephrology colleagues and all the other team members, to improve their medication management. Dr. Agarwal and Dr. Richardson both noted that there are a number of new therapies that demonstrate significant reduction in CKD progression and reduce CKD risk. So we have to identify patients and get the medications into the hands of patients that need them. And today, CMS recognizes us and we have new value-based care models in kidney disease that opened up new opportunities for pharmacist roles. Thank you.

Dr. St. Peter and the distinguished faculty will provide insights and clinical pearls to help achieve the goals of improving the clinical and economic consequences of diabetic kidney disease.

Wendy L. St. Peter, PharmD, FCCP, FASN, FNKF : Now, I would like to bring my 2 esteemed colleagues together to join me to talk a little bit more about some of the topics we touched on during our presentations. And I wanted to focus my first question on Dr. Agarwal. As you pointed out, we now have 3 approved therapies for reducing progression of kidney disease. The majority of patients in the SGLT-2 inhibitor trials, the finerenone DKD trials were on ACE inhibitors and ARBs at baseline. Considering efficacy of both of those classes of drugs, which class, SGLT-2s or finerenone, should be considered first in patients with DKD. And then secondarily, what are the key monitoring parameters that you want to think about when adding either one of those to an ACE and ARB?

Rajiv Agarwal, MBBS, MD, MS, FASN, BRCU: Great question, Dr. St. Peter. I think that we are now in the same place that perhaps we were with heart failure therapies or with antihypertensive therapies, when there were more and more classes that came out. We initially, for example, with the blood pressure guidelines, we had a sequencing approach. You had a step care approach. And then we went to a combination therapy approach. While I don't know how the guidelines will define this, I think we have a great opportunity here to fine tune our therapy to the needs of our patients. As you pointed out, everybody needs to be on an ACE or ARB as a background therapy. But once we have satisfied that requirement, because all the trials did that, we have to ask, which of the 2 therapies, nonsteroidal MRA, or a SGLT-2 inhibitor, given what I know about the patient's physiology and pathology, would fit best?

For example, a patient who has, say, hypokalemia, potassium might be 3.4, 3.5. I would probably use a nonsteroidal MRA because it's going to raise potassium. Whereas if the potassium was 5.2, I'd say, "Well, nonsteroidals are contraindicated. We'd probably use an SGLT-2 inhibitor." If the eGFR was less than 25, neither one of these 2 drugs would work. But important to note that, if the eGFR has gone down from, say, 45 and it's declining, and the patient has an eGFR of 15 or 20, it's not an indication for stopping either drug. We continue to give the drug. We don't stop it just because the eGFR has declined.

Wendy L. St. Peter, PharmD, FCCP, FASN, FNKF : I want to make sure that pharmacists understand this point, that if you have somebody that has an eGFR less than 25, neither of these sets of drug classes do you initiate the drug. But if they're on it and reach below that, you can continue all the way to dialysis.

Rajiv Agarwal, MBBS, MD, MS, FASN, BRCU : Absolutely. Very good point. I get call all the time, "Hey, we stopped the drug because the eGFR fell to less than 25." Well, if you read either one of the package inserts, they don't say that. They say, we don't start if the eGFR is less than 25. In a patient who has recurrent UTI or fungal infections that they might have experienced with SGLT-2, it's very hard for the patients to go back on those drugs. In fact, the patients say, "Doc, I know what you're talking about. I don't want to go back taking this drug which caused it." So if the patient is not going to take the drug that you're prescribing, you probably have to choose an alternative. So I think we will have to make a choice. But ultimately, both drugs would work better together. So you'll have triple drug therapy for most patients.

In particular, what we have seen in trials is that when you use the 2 drugs together, the propensity to get hyperkalemia is less. So people who are getting the combination of SGLT-2 inhibitor and finerenone, they're probably less likely to get hyperkalemia. I presented an abstract at the World Congress of Nephrology meeting a few months ago, and these were data from FIDELIO trial. And what we showed is that people who are on baseline SGLT-2 inhibitor, they had less likelihood to get hyperkalemic. Another group that can benefit is people who are on diuretics. If they're on diuretics, they're less likely to get hyperkalemic at baseline. So I think we will have to use our clinical judgment, which goes first. But ultimately, I hope that most patients will get all 3 drugs.

Wendy L. St. Peter, PharmD, FCCP, FASN, FNKF : And I think now that finerenone is on the market and clinicians will get them into their hands and start experiencing, we'll start seeing information coming out on the literature about practical ways of how these drugs can be monitored and dosed when they're used together. So hopefully though, that kind of information will start appearing shortly.

Rajiv Agarwal, MBBS, MD, MS, FASN, BRCU : Just to make a point, the package insert has very clear guidelines on how to monitor potassium. They have to come back in 4 weeks and then periodically thereafter. Only if the potassium is more than 5.5 that you hold the drug. And when you hold the drug, you recheck it and you can start it at a lower dose. So I think it's really important to see the potassium in these patients. The guidelines on how you start and stop, they are a little complicated, but you have to know those numbers when you start using the drug.

Wendy L. St. Peter, PharmD, FCCP, FASN, FNKF : I think it will help too when guidelines, like KDIGO, will also incorporate those into guidelines too and put some of that information out there. It is hard to keep track of all that. And so certainly alerts, I think Dr. Richardson, you really pointed that out. Those helpful alerts in EHRs are really important. Can you speak, Dr. Richardson, to how community pharmacists, particularly those pharmacists that offer enhanced services, are ideally positioned to identify patients with CKD, using some of the tests we talked about and doing things like med rec and review?

Michelle M. Richardson, PharmD, BCPS : I think there's a lot of opportunity in those situations where they're more likely to see the patients more frequently than, as you said, primary care or even nephrologists. So that one, the frequency of contact, certainly makes teaching about the disease and its silent nature easier, because it's small bits over time. Also, having those tests right there so that a patient isn't leaving a primary care physician's office and having to go to a laboratory or having additional steps. So it becomes a 1-stop for what they need. I think also, the pharmacists have ready accessibility to information, whether it be the guidelines, the package inserts. They can appreciate these complex differences between initiating and continuing therapy. They're also going to be aware when maybe it's not a PCP who's discontinuing something, or maybe a nephrologist is adding a medication that the PCP doesn't know about. So the pharmacist has information upon which they can make at least initial judgments about what's going on.

As far as identifying patients at risk, certainly someone who comes in with any treatment for diabetes is automatically an at-risk person for CKD. So right there could be a trigger to either refer the patient to various sources of information, depending on who they are, their health literacy, what they know about their other diseases. And then I think, as you both have mentioned, as we think about the treatments to inhibit the progression of CKD, things are getting more complicated. There's more and more medications. There's more and more monitoring. And there has to be the central person who's readily available to patients to be able to address those things. And I think pharmacists are well positioned to be able to do that.

Wendy L. St. Peter, PharmD, FCCP, FASN, FNKF : I just wanted to discuss how pharmacists can help close that gap in the shortage of both primary care physicians, as well as nephrology, not only physicians, but nephrology nurse practitioners, and how that could help practices incorporate better comprehensive medication guidelines.

Rajiv Agarwal, MBBS, MD, MS, FASN, BRCU : I think that it's really important to screen these patients. I think, as it was pointed out, we have point-of-care devices now. One of the things that really needs to get on board with these patients is screening for kidney disease in presence of diabetes. The national statistics show that only 1 in 5 patients has been screened for albuminuria when they have diabetes. The guidelines tell us they have to have annual screens. It's not happening. And now, we have these amazing trials that show that you can screen, but now you can do something about it. It's not just an academic exercise. A lot of primary care physicians used to ask, "Okay, what would I do with that information if I find albuminuria?" Well, you can prescribe these medicines. They are indicated based on that result itself. Don't wait until the eGFR starts declining, because albuminuria is one of the earliest markers.

And it's the lucky people who get dialysis. Most people die of cardiovascular disease. So if you really want to impact cardiovascular health in these people, it's to screen for albuminuria, which is really, really simple. It can be done by any point-of-care device. It doesn't even need a blood draw. And I think that's where pharmacists can really have a great role. The other place I see is that oftentimes, these therapies are stopped. Just the other day, one of my patients said, "Well, they stopped my SGLT-2 inhibitor because my glucose dropped." I say, "If your glucose dropped, they need to reduce your insulin, not stop your SGLT-2." Here, really, the pharmacist can help and say, "Hey, if you are on a GLP-1 RA or SGLT-2, they're not just glucose lowering drugs, they are protecting your heart and your kidneys. And you need to address the insulin and lighten up on that instead of messing around with these 2 therapies.

And as you pointed out, I think these are very important tools that the pharmacist can provide to the primary care physician. If we have to make a dent in cardiovascular disease and kidney disease health in people who are living with diabetes, we have to move upstream. We have to involve everyone. We can't just be dependent on endocrinologists, cardiologists, and nephrologists. We will need pharmacists, we will need primary care physicians, and we will need to educate the patient and say, "What is my number, doc?" Just like they said, "What is my number for cholesterol? And what is my number for blood pressure?" They are to be asking the doctors, "Doc, can you check if I have kidney injury?" I think that's off the radar screen. If we don't educate the people, we're going to not make a dent in this massive epidemic.

Michelle M. Richardson, PharmD, BCPS : To add to that, and I completely agree with all of Dr. Agarwal's points, more people have access to a pharmacist and closer proximity than they do a physician, particularly in less populated areas of the country. And so by recruiting everyone and making this just be something that all adults who are at risk do on a regular basis to meet the... The guidelines are based mostly in science and we're not meeting those guidelines, particularly with screening. So whatever we can do to help move that forward will make a significant impact in all of the consequences of kidney disease.

Rajiv Agarwal, MBBS, MD, MS, FASN, BRCU : Michelle, I couldn't agree with you more. It takes a village. And there are only 5,000 nephrologists in this country. And I'll tell you, the cardiologists don't want to bother with glucose lowering drugs. It's outside their domain. I think the pharmacists are uniquely positioned to intervene because they understand the medications, they understand the drug interactions, they understand insulin, they understand what GLP-1 RAs are, SGLT-2 inhibitors are. And sometimes, the primary care physicians can be overwhelmed because of the caseload. I don't think that this is going to go away unless we use every possible resource and float everybody's boat here.

Wendy L. St. Peter, PharmD, FCCP, FASN, FNKF : Well, I want to thank both of you for this wonderful discussion. And I just wanted to wrap up with just 3 key messages. Chronic kidney disease is widespread. It hasn't been identified to the degree it needs to. We have new tools in our shed to be able to treat patients' kidney disease progression. And I think all of you said, we need all hands on deck to do that, including pharmacists, to actually make a dent in the CKD progression that we see today. So thank you so much for providing such amazing, good information today, for a pharmacist listening to this.

Michelle M. Richardson, PharmD, BCPS : Thank you.

Rajiv Agarwal, MBBS, MD, MS, FASN, BRCU : Keep doing the great work, pharmacists. We need you.