Dr Chuck Vega (UC Irvine School of Medicine): I am just going to have fun for a second. I am going to draw us back to this slide. So staring at it for a few minutes.

And I like sports, and I cannot figure out what play and what sport that diagram is trying to signify. But then I thought about it for a second, I realized this is not a set play, but I used to coach my kids in everything, soccer, basketball, football, and every play in those sports when they were 5 or 6 years old, or 3 to 6, turned into that. Just a bunch of kids swarming together. One wants the ball. The other is very afraid of the ball. This one down here is going for a stuffed animal on the side.

My daughter played a full season of soccer, her first season of soccer with a stuffed animal in her hand because it is the only way she would play. And I thought, oh, this is kind of a signature. If you get really good, you can kind of have a following.

But she played 1 more season, and that was that. She lost her stuffed animals. She lost her magic. She never went back to soccer again. I use sports. So that is my lead-in.

[00:10:16]

Spotting CKD Before It Strikes: Importance of Early Detection and Intervention<

Let us actually talk about a disease, chronic kidney disease, that is.

[00:10:20]

US Prevalence of CKD Through 2020

So you can see the prevalence. You would think that the prevalence of CKD, I will let you look at the numbers. I mean, certainly we see a high prevalence overall, about 14% of US adults, which is really similar to what we see with type 2 diabetes, with hypertension, with the new guidelines that were put out by ACC/AHA, 45% of US adults have hypertension based on those guidelines. Many of them do not know it. And many patients with CKD do not know it either. A significant, at least 30%, do not know they have CKD. You would think the rates would be rising up with obesity going higher, diabetes going higher, hypertension going higher. Why is not it?

Well, because we as clinicians have more options to treat CKD, so, we are seeing less of the stage 3 CKD and certainly stage 4 and 5. For years and years, we just really had, when it came to specific interventions to reduce the impact of CKD, it was ACE inhibitors or angiotensin receptor blockers, ARBs. And now I am going to go over, we have 3 different options that can make a difference.

And so, while we see higher rates of the diabetes and hypertension, which account for about 80% of chronic kidney disease in the United States, we should be heartened that we are actually not seeing, I think, a dramatic rise in the rates overall. And that is a lot of, I want to encourage everybody, including myself, in an hour and a half to really take this problem seriously and keep treating patients because we know it is making an impact. It really is helping with morbidity and mortality over time.

[00:11:53]

Kidney Disease Facts: US Population

We also want to practice equitably. So we know that African-Americans, by genetic factors and by sociodemographic factors, have the highest rates of chronic kidney disease in the United States.

Unfortunately, represent way too many folks on dialysis in proportion to the percent of the general population, which is about 14% of us adults identify as Black or African-American, but 30% of those with kidney failure are Black. See higher rates among Hispanic and Asian adults as well. And I would also call out Alaska Natives and American Indians, also very, very high rates of CKD and kidney failure.

These are all folks who are predisposed to getting diabetes. So if you look at non-White populations in the United States, higher rates of diabetes equates to higher rates of kidney disease.

It is a leading cause of death. There is a ton of morbidity associated with it. And yes, it is at least two thirds of all new kidney failure cases, about 80% of CKD overall is related to type 2 diabetes or hypertension. But we will talk about how the fact that that is 20%, that at least 20% that is not going to be related to diabetes and hypertension.

So while we, I think I will focus on DM and hypertension a lot during this talk, we will go over some other causes as well.

[00:13:10]

CKD as a Multiplier of Health Risk and Cost

So in terms of stages, I think 1 of the meaningful things when we think about the long-term prognosis of patients with CKD, I work at the biggest safety net clinic here in Orange County, and my patients with CKD have done pretty well over time. I have a lot of folks, having practiced in the same place for nearly 30 years now, that between the ages 50-80, I like to say that we have kind of walked this path through the cardiovascular valley of death together, you know, because the patient has obesity, hypertension, diabetes, hyperlipidemia, all those risk factors, but they did not have the big MI, they did not have a stroke, but they did have CKD, but we managed it. And now, they are 81, they are at CKD 3B, but they have been there for the last 15 years. Their diabetes is not as severe because they are eating less and their kidneys are not working as well. So they are holding on more to their natural insulin. So that is heartening. That is the good news is that I am worried about them dying related to kidney disease, but there is still an increased cardiovascular risk.

Remember that when you think about CKD and the risk factors for CKD, it is also an independent risk factor for cardiovascular disease. And that is, of course, what is eventually what kills most patients with CKD is cardiovascular disease. So we really want to max protect them.

And I have got a nice slide. It is a busy slide, but it just emphasizes a multimodal approach treatment for these patients, because when you see kidney risk, think cardiovascular risk, they go really like hand in hand. And the worse your kidney stage is, the higher cardiovascular risk, both your eGFR, which is the glomerular filtration rate, which is a measure of the kidney's function, as well as the UACR, which is really looking more at the microanatomy of the nephron and is it still intact or are people losing protein. When either 1 is positive, cardiovascular risk goes up. When both are positive, cardiovascular risk goes up.

[00:15:10]

Elevated CV Risk With vs Without CKD: Unadjusted Incidence Rates and Risk Differences per 1000 Person-Yr

And so this slide is really looking at a population-based study that showed the same: heart failure is intimately linked with chronic kidney disease as a CHD, and to a lesser extent, stroke. And so, therefore, we want to max protect individuals with chronic kidney disease, and I will go over that shortly.

[00:15:30]

Risk of CV Death Increases With CKD Severity

The worse the stage, the higher the increase in severity.

If you look at folks with existing cardiovascular disease, at least 38% have chronic kidney disease as well. So it is 1 of those common cardiovascular risk factors is a modifiable risk factor, because my whole goal is to prevent patients from making this progression, this march towards worse kidney function over time. And so, then we will talk about how to do that.

[00:15:59]

Risk Factors for CKD

So other things. This is the slide where I am going to highlight other factors. So certainly if your patient has a history of severe nephrolithiasis and 1 of their kidneys is non-functional due to prior blockage, or just even any kind of severe obstructive uropathy can result in chronic kidney damage, and maybe they have hypertension too. That is going to add to it.

What if they have lupus or 1 of the other autoimmune disorders that affects the kidney? That could do it. We can cause problems ourselves many times with chemotherapy or other drugs that are nephrotoxic, contrast materials used. So we really want to be judicious with the use of those medications and when we choose our imaging. And there is definitely a genetic component. So just having a family history of kidney disease is a reason to screen for folks.

We will talk about this APOL1 gene that particularly affects African-Americans and does increase the risk of kidney disease, regardless of the presence of hypertension or diabetes. So it is, this is something when you have a family history with, you know, a brother on dialysis and the mother on dialysis, even if there is not diabetes or hypertension, those patients should be screened for kidney disease. And I would send them also for genetic counseling for APOL1.

And then occupational exposure, another potential issue, we see a lot of unregulated workplaces here in Southern California. And if they are exposed to chemicals, that could be dangerous. Nephrotic syndrome is very dangerous, both for the kidneys and for the heart as well.

And so we really want to pay attention to these other things. And just like anything else, the more of these factors that you have that are negatively impacting your kidneys, the worse your prognosis. So I just want to keep an open mind for these patients.

When I see patients where their GFR is declining, it is going down, and they have mild hypertension that is well-controlled, and that is it. And I have them on, say, an ARB and maybe an SGLT2 inhibitor. And yet I am not seeing them responding, that is when you send the renal. Those are the folks that probably have something else going on, getting ultrasound of their kidneys. And as you do so, and then they can get that done before they see the nephrologist. There is probably another factor that they have. And some of these patients need a kidney biopsy to really cinch that diagnosis.

[00:18:22]

CKD Often Goes Undetected Because Symptoms Are Not Evident Until Disease Is Advanced

Most folks with chronic kidney disease do not know it. Just remember, this is 1 of your first questions, like, gosh, what are the potential symptoms? Well, it is a lot of volume overload, right? And it actually starts with something even more vague, which is just fatigue, just feeling tired, having exercise intolerance.

That is what you might see at stage 3 CKD. Then, as it progresses, anemia is pretty common as erythropoietin levels go down. And so they might see even exacerbations of that, but by that time they are having edema, they are having shortness of breath, they are having electrolyte abnormalities. That is not till stage 4. It is very rare to see symptoms when the GFR is 30 or more. So think about stage 4. And they are usually subtle symptoms, but they are there. They can look a lot like heart failure. And many of these patients have by that time developed heart failure.

So you really want to be thorough and get a brain natriuretic peptide or BNP, or even an echo. And you also are going to really want to dig down and try to control kidney disease. Because by the time they are symptomatic, you are really talking about significant risk. And again, kidneys and heart together.

[00:19:34]

Key Goals of CKD Care

So our goal is to find the kidney disease. We have good tools to slow the progression of kidney disease, starting with patient's lifestyle, right through multiple different medications, and that is going to optimize outcomes.

[00:19:46]

Call to Action for Primary Care

So we have to screen. We have to screen patients. So if you see patients with diabetes, you probably know you are not just supposed to get at least an annual eGFR, but you are supposed to get a UACR, urine albumin creatinine ratio. It is called different things, microalbumin, things like that. UACR is the accepted term. And I think there is greater coalescence.

Unfortunately, a lot of our patients with diabetes, are getting a GFR, over 80%. Only about 25% get an annual UACR. So we really need to say, it is your urine and your blood test. They both contribute.

And for patients with more severe disease, or it is progressive and you are watching trends that do not fit in with your normal, slow increase in those abnormalities over time, you can get them certainly more frequently than every year. I have some patients where I am getting a urine test every 4 months because I do see a normal amount of proteinuria right off the bat. And a lot of times I am thinking in the back of my mind, this might need an urology consult as well, because I have them on maxed out therapy as well.

So once you get the eGFR and UACR, that is how you are going to diagnose CKD. Then you are going to put them in the right stratification. In terms of risk, we have the heat map coming up. I will show you that. And then initiate treatment. And you may think about referral.

I actually manage most patients with CKD absolutely in my own practice, but we will talk about when to refer.

[00:21:10]

2 Tests Are Better Than 1: CKD Screening Protocols for Primary Care<

So 2 tests are better than 1: CKD screening protocols for primary care.

[00:21:15]

Poll 3: How confident are you in identifying patients who should be screened for CKD?

So let us go to a polling question now.

Tracy, are you ready to join in?

Tracey Piparo: Here we go. So I am sure you guys have been listening. How confident are you in identifying patients who should be screened for CKD?

1. Not at all confident;
2. Somewhat not confident;
3. Neutral;
4. Somewhat confident; or
5. Very confident.

We want your honest opinions here.

Dr Vega: I would say if you feel like you are somewhat not confident, I agree. That statement says you are not very confident.

Tracey Piparo: Be sure to hit those "Submit" buttons.

Well, it looks like a decent amount of people are somewhat confident. I am sure you are going to give us some information about that.

Dr Vega: Yes, no, that is great. But we saw like, you know, maybe the 34% with the, you know, kind of in that neutral, maybe a little less confident range.

[00:22:12]

2024 KDIGO Screening Algorithm for CKD: eGFR and UACR

So yes, the good news that we have is I talked about how diabetes, I mentioned the rules specifically to there that you really want UACR and eGFR at least annually. Well, guess what you are going to do now for hypertension? Same thing. Europeans have been doing it.

The newest guidelines from ACC AHA, which came out a few months ago, now advocate for checking UACR. Before it was elective, now do it. It is covered. I have never had a problem getting it covered as a test. It is not that expensive a test. And again, it is additive information when you get that UACR.

So say if your GFR is normal, as I show you, but you have significant proteinuria, your kidney disease risk, your cardiovascular risk are still high. So we really want to check for both. I will talk about Cystatin C in a second. I do not know if you use that. It is not as widely available. It is a little more expensive. It has had a slow rollout. I will get into all the reasons for it. And I do not use it in every patient, but I do use it in certain patients.

The key here is that you want to, though, I think, repeat testing. So if you have a GFR that puts them in the CKD range, and generally what I really worry about is GFR less than 60, that is going to put them in that CKD 3A range when they are 60-45. And that is where you start to see a significant disease increase.

So if they are 72 vs 85, I think that is generally a good kidney function, depending on the patient. But yes, getting the urine is going to be very valuable as well, but there are a lot of patients with acute kidney injury. Maybe they just had a virus. Maybe they just took a bunch of NSAIDs because they had back pain. There are a lot of things that can throw off your eGFR particularly. And so repeat it.

When you get 1 that is abnormal, before you can make the diagnosis, you really have to repeat it. If it is grossly abnormal, you are going to repeat it more quickly. If it is mildly abnormal, you are just going to do a test. If it is mildly abnormal, you are just going to repeat it. Usually right before your next visit in about 3 months. And so use both tests, prioritize those patients.

If they have another big group, if they have preexisting cardiovascular disease, remember, and they do not have a UACR on chart, that is another reason to get it. So it is just going to help risk stratify them a little bit better if they have a family history of kidney disease. All of those patients are the ones you test.

Mostly I do it for hypertension and diabetes, which covers a very significant proportion of adults overall in the United States. And because if you work in primary care, it is probably the majority of patients in your clinics who are 50-80 are going to have 1 of those conditions just because you are a healthcare provider. That is your job.

[00:24:47]

Improving Equity in CKD Screening

All right. So GFR equations currently do not contain race. This is old news because that was done away with 4 years ago after some years of controversy.

So what about cystatin C? So cystatin C is not just in muscle cells, it is contained in all cells. And therefore, generally, it is a better marker of CKD. I find that the problem was trying to calibrate the devices in terms of how they measured it, and then using it in the equation, so you got a reasonable and consistent result, that took some time, actually, and it still is more expensive. But I am able to get it, and I get it in a few cases. One, it is all about with creatinine and its clearance. That has a lot to do with muscle mass, right? If you have a lot of muscle, if you are using creatine, you are going to be producing more creatinine. Your serum creatinine is going to be higher.

So very muscle-bound individuals, and I am screening them, cystatin C makes sense. Probably more pertinent in my practice, a lot of older adults who have very little muscle mass, cystatin C can also be very helpful because those folks may have a normal eGFR because their heart, their creatinine levels are very low in their blood overall. And that is why I combine it with the urine, which does not depend on those things.

But I would also call out cystatin C if you have uncontrolled thyroid disease. Do not check a cystatin C because that is something that can throw that level off. You want to control their thyroid illness first. So cystatin C, when you are unclear, can be a really good tool to use.

And then think about getting this APOL1 mutation tested. It is estimated about 13% of folks of African-American heritage in the United States are carriers of this gene. And it is a recessive gene, but it can have an effect on renal risk, even among heterozygotes and much higher among homozygotes. And so really take a look, if they have got a family history, it is about a quarter of individuals. Many of my patients unfortunately do not know about earlier stages of kidney disease, but they know when a relative went on dialysis. And so use that.

[00:27:11]

Diagnosis/Risk Stratification Requires eGFR and UACR

Use this as well. This is your heat map. Maybe you have seen this before.

This is from the KDIGO, which is the international body that makes annual recommendations regarding screening for and managing kidney disease. And I will just call out that you could have 1 of these very benign stages of GFR where your GFR is 88. But if you have significant proteinuria, more than 300 mg/g, that is on the right there, you are already in the orange category.

Orange category, these categories work very well for cardiovascular risk and for renal replacement risk. So you are at higher risk for dialysis, you are at higher risk for a heart attack or a stroke if you get in that A3 category. So again, I am just really trying to drive home the fact that get the UACR, it is additive beyond just getting the GFR in terms of stratifying folks for cardiovascular risk, and it is going to change the way you treat them.

So it is not like you can just throw up your hands and say, oh, well, you are at higher risk. Sorry. You know, good luck.

We are actually going to do something about it. Patients can do something about it through changing their lifestyle. We can do something about it as clinicians because we have got a bunch of pharmacotherapy.

And by the time, unfortunately, you are down with stage G4 chronic kidney disease and elevated proteinuria, you are at high risk. But remember, everybody gets rechecked within a few months, regardless of their levels. When I do recheck – I get a lot of new patients; they do not know they have kidney disease – it turns out they are already in stage G3B with significant albuminuria. I recheck them. Does it change a lot? No. Usually it is. It has been there. They just did not know. But now we have got the knowledge. We can improve their outcomes. I will talk about how.

[00:28:54]

“Stop (Disease Progression), Collaborate, and Listen!” Actionable, Patient-Centered Management of CKD in Primary Care<

So let us stop, collaborate, and listen. Sounds a lot like vanilla ice. Let us go to actual patient-centered management.

[00:29:06]

CKD Treatment and Risk Reduction: A Holistic Approach

All right. So do focus on lifestyle. It makes a difference. So healthy weight, healthier for the kidneys. More plant-based diet, awesome. Stopping tobacco products, awesome, awesome. All good. And my nephrology friends were always a little bummed out because for about 30 years, they had this problem in front of them: mounting rates of chronic kidney disease. And they really had 1 therapeutic option, RAS inhibitors, either an ACE inhibitor or an ARB.

And so you want to use those. Those are still first-line agents. So once you detect kidney disease, lower GFR, UACR-positive, go ahead, and you are going to treat with an ACE or an ARB. I have got a slide comparing the 2, and I will maybe give a little bit of color there in a second. But that is important.

But then lo and behold, SGLT2 inhibitors came on board. And it is like, wow, these drugs are great for diabetes. They seem to be effective in addition for kidney disease. I wonder if you can use SGLT2 inhibitors among individuals with CKD that is not related to diabetes. Maybe it is due to hypertension, or maybe it is due to nephrotic syndrome.

Yes, they actually do work. Both ACEs and ARBs use different means, but actually have the same ultimate mechanism, which is decreasing intracranial pressure, which helps function over the long term. It helps with the anatomy because the nephron stays intact. The podocytes stay intact. And so, therefore, you are going to see lower rates of proteinuria, or at least they will not be getting worse. And the function of the kidney as a filter overall therefore improves, so the GFR stays more stable.

So SGLT2 inhibitors can get you there. ACE inhibitors and ARBs can get you there. And then there is another drug too called finerenone. Finerenone is that non-steroidal mineralocorticoid antagonist. That is newer, just in the past 5 years, but it has some really good outcomes. I will share it with you as well.

If you can get all 3 on board, we will talk about how the fact that you are going to make a significant difference in this patient's cardiovascular risk and their renal risk. But do not forget, we cannot always get all 3 of those on board. I will talk about limitations, but that is why you really want to control other risk factors.

So you really want to be aggressive with lipids here. Endocrine Society says you have CKD, you have diabetes together, your goal LDL is less than 70. So kind of like somebody who has preexisting cardiovascular disease, you really want to push them down and push the blood pressure down. You want to get it really under 120 if you can. For my 88-year-olds, maybe that is not as much of a priority, but for my 60-year-olds, absolutely. I really want to push.

So maybe we cannot get all those 3 agents that modify kidney and cardiovascular risk on board, but I can certainly try to push down all their other cardiovascular risk factors, body weight too, all those things. So there is a lot. I am not going to go through all of them.

[00:31:58]

First-line Treatment for Slowing CKD Progression

So including watching diet, so really avoiding ultra-processed foods is probably the biggest key. Really trying to be plant-based is, and this is broad terms, how patients want to do this, catering to their favorite foods, catering to their culture and values, but really want to get those through.

You want to have protein intake. If you are at CKD 3, I am not too worried about your protein intake. In fact, even at stage 5, I am not too worried because most folks do not get that through their diet.

Just be careful of supplements. I actually just went through this with my own parents, who are over 80. Happy birthday, Mom. It is her birthday. Call her later. But yes, they were asking like, well, should I be taking more protein?

And it is like some of the ads on television, I watch a lot of old person television, and it is like, yes, we were packing 120 grams of protein in this little shake. It is like, no, if you are using 3 of those a day and you have CKD stage G4 or worse, yes, you can do damage. So I say probably your diet, you are not going to get that much protein, and it is healthy for muscle. It is probably not going to affect your kidney negatively, but if you start using supplements, I just get worried, especially among older adults. Exercises, guess what? Good. And yes, losing weight's important.

[00:33:18]

Patient Case 1: 66-Yr-Old Woman Presents to Primary Care for T2D Follow-up

So we have a few cases to go through. I am going to start with a 66-year-old woman who presents to primary care for type 2 diabetes follow-up.

She has had diabetes for 15 years. She has some hypoglycemia in the morning, hypertension, dyslipidemia, there is her BMI. There was some concern regarding kidney disease at last year's visit.

She is on metformin, glipizide, losartan, or atorvastatin. Her blood pressure is 128/82. Her heart rate is 78. Her A1C is 7.6%. Her UACR is positive, strongly, 288 mg/g. Her eGFR reduced mildly or moderately at 54. Her K is just 3.9. Her cholesterol values you see there with an LDL of 90.

[00:33:57]

Poll 4: What type of medication(s) would you add to this patient’s regimen based on recent KDIGO guidelines? Please select all that apply.

So let us get to a question for you all. What type of medication would you add to this patient's regimen based on recent KDIGO guidelines? You can select all that apply, so you can select more than 1.

Tracey Piparo: Yes, so your choices are going to be:

1. An ACE inhibitor;
2. GLP-1 RA;
3. Insulin;
4. ns-MRA; or
5. SGLT2 inhibitor.

Do your best with these, and let us learn more about all of these.

Dr Vega: Yes, so it looks like the popular ones were ACE inhibitor and SGLT2 was definitely the most popular. She is on losartan. You do not need that; she is good. She has got that under control. So do not use ACEs and ARBs together. Really, there is little benefit, but a lot of side effects.

But SGLT2 would probably be a good choice. You could certainly, and I would think about using a GLP-1 as well if I had access to it, for sure, because that is, and I use that to replace the glipizide, which is going to promote hypoglycemia weight gain and does not help her kidneys at all.

[00:35:18]

First-line Pharmacotherapy Recommendations for Most Patients With CKD

So RAS inhibitors, absolutely. These are still foundational drugs. I like ARBs better than ACEs. They do not promote cough. 10% of patients with ACEs develop a cough and a tenfold reduction in the risk of angioedema, which is the worst thing that can happen with an ACE or an ARB. In terms of how effective they are, it is equivalent. How much hyperkalemia they cause, it is equivalent. But yes, for those reasons, my patients generally get an ARB over an ACE.

SGLT2 inhibitors, I will go into some of the data, but you can use them even down to very low eGFR levels. Particularly if there is heart failure, there is really no limit anymore to how low you will go because they are so effective in heart failure for preventing outcomes like hospitalization.

So that is a very good choice as well. And that is probably where I would start. Could you start a GLP-1 and SGLT2 at the same time? Yes, absolutely. Absolutely. You can do those at the same time. But yes, if your patient is really sensitive and scared, I would probably say SGLT2. And then the next visit, think about that GLP-1.

[00:36:16]

ACEi vs ARB: No Difference in Glomerular Filtration Rate Decline

ACEs or ARB, no difference in terms of their function or their effect on glomerular function. But I do like ARBs because of the side effect profile.

[00:36:27]

FDA-Approved SGLT2 Inhibitors

And SGLT2 inhibitors, the big ones that have the real indication, canagliflozin, dapagliflozin, and empagliflozin. Choosing between them, mostly comes down to insurance and what that prefers. Because if you can get any of them on board, especially those big 3 that have the real indication, it is going to be very helpful. They are all well-proven in terms of improving not just the kidney outcomes, but the cardiovascular outcomes as well.

[00:36:51]

SGLT2 Inhibitor Impact on Kidney Failure in CKD Trials

And this is looking at how they work with and without diabetes. So those big 3 are favored. We know through very large trials that they are effective at slowing the decline in GFR, reducing the risk of renal replacement therapy in diabetes, and also without diabetes. They are pretty well accepted as well. Therefore, they are foundational drugs along with ACEs, ARBs for patients with chronic kidney disease.

[00:37:18]

Patient Case 2: 72-Yr-Old Man Presents to Primary Care for Annual Follow-up

So let us move to our next case. Now we have hypertension, dyslipidemia, and diabetes in a 72-year-old man, obesity at stage 3aA2 for 8 years. So that means a modest decrease in GFR, but also some significant proteinuria. On losartan, hydrochlorothiazide, you check that box. sitagliptin and empagliflozin, check that box. Metformin and atorvastatin. Atorvastatin, too, I would say for this gentleman, check that box. You really want a high potency. You would have to tell me why we are not using a high-potency statin in this patient given their cardiovascular risk. Blood pressure is a little higher than we want. Truncal obesity, GFR is 42, UACR 232, creatinine is 2.3, potassium is 4.3, AST and ALT are slightly elevated, not a shocker. A1C is 8.5%.

So kind of fix this in your mind. It is a little hard. There is a lot to recall there, but let us go to our polling question.

[00:38:19]

Poll 5: Which of the following would you recommend to improve glycemic control for this patient?

Tracey Piparo: So which of the following would you recommend to improve glycemic control for this patient?

1. Add insulin;
2. Add a GLP-1 RA;
3. Discontinue sitagliptin and add a GLP-1RA;
4. Discontinue all glycemic control agents and transition to insulin.

Dr Vega: This one has a right answer.

Tracey Piparo: Everyone's going to try their best.

Dr Vega: Yes, and there is only one. We cannot mark multiple.

Tracey Piparo: That is a pretty decent majority there.

Dr Vega: Yes, I think I am feeling where you want to go, but remember they are on sitagliptin. So can you use sitagliptin and a GLP-1RA together in the same patient? Yes. Should you? No. It does not make any sense.

So just remember our DPP-4 inhibitors like sitagliptin, they are the golden retriever of antidiabetes medications. They get along with everybody. Everyone likes them. They are very benign, but then you look at it lying in the sun, and it is like, what are you really doing here? They do not really do much. They are not good at lowering glucose. They have no cardiovascular or renal benefits. So yes, if you need a very mild, well-tolerated drug, choose DPP-4. If you actually want to do something in terms of improving cardiovascular risk, renal risk, obesity, and diabetes with an A1C reduction along the lines of 2% with semaglutide and tirzepatide, use your GLP-1.

But yes, there is no point using them together. You are not going to hurt them, but yes, the injectable GLP-1s particularly are very, very effective.

So again, that is them. The FLOW studies show that semaglutide was effective in chronic kidney disease outcomes. The drugs can seem like they can do everything, but they are just really great choices. So especially if you can replace something like insulin with a GLP-1, I love doing that. No hypoglycemic risk. They are going to lose weight, not gain weight. So important for a patient with hypertension and diabetes. So yes, there are a lot of benefits.

[00:40:23]

Second-line Pharmacotherapy Recommendations

You may or may not be familiar with non-steroidal mineralocorticoid antagonists. This is different. They are not spironolactone or eplerenone. They are non-steroidal, so, therefore, they avoid the side effects. They also promote less hyperkalemia, which is the rate-limiting step for me with using those 3 agents, SGLT2, ACEs, ARBs, and eplerenone together, as many times, the potassium may not support that. It is over 5.5, but if it is stable at 5.3, roll on. You are going to get good renal protection, and I am not worried about a stable potassium of 5.3 in terms of side effects. I may not start at their Ks over 5, though, because that is still a risk factor with finerenone, but we will go over some data.

[00:41:06]

FIDELITY Pooled Analysis of Finerenone

This is FIDELITY, and these are the 2 trials that looked at, they were called FIGARO-FIDELITY, and they looked at when putting the outcomes together, you can see that adding finerenone to patients with diabetes and eGFR over 30, and was associated with not just kidney outcomes, improved the risk of cardiovascular death, for example. Particularly for heart failure, finerenone is very effective, just like the SGLT2 inhibitors, where they really have their best cardiovascular effects has on heart failure and those outcomes, which are really serious outcomes, morbidity and mortality associated with those, but it also improved kidney outcomes.

It is another 1 of these dual-benefit drugs, heart and kidneys together, when you can add finerenone to that regimen. For that patient, I would say, yes, adding an SGLT2, they are already on empagliflozin, adding a GLP-1 would be really important.

[00:42:00]

FLOW: Semaglutide (GLP-1 RA) for Patients With CKD and T2D

This is that FLOW study looking at the composite kidney outcome over time, greater than 50% reduction in eGFR or renal replacement therapy. Semaglutide was outpacing placebo with those. Over time, over the trial period of 4 years, you can see those curves widening out a little bit, so an overall 24% reduction in that hazard. We know about the cardiovascular benefits of drugs like semaglutide too, so much better choices. Basically, these days, if you have diabetes and hypertension, I am able to get them on an SGLT2 and a GLP-1. I feel so much better about their cardiovascular and their kidney outcomes over time. They are going to be better treated.

[00:42:38]

Pillars of Treating Patients With CKD

This slide is a graphic way to say these are the pillars now. Really, before there was 1 agent, now we have really 4. If you throw the GLP-1 or GLP-1-GYP in the case of tirzepatide into the mix, you have 4 pillars of treatment. When you add these pillars together, you make a stronger foundation for the patient's kidney and cardiovascular health, good things happen.

This is a modeling study looking at population-based data. You can see that if you are able to get those big 3 onboard, GLP-1, finerenone, and SGLT2 inhibitor, you really can reduce the risk of CKD progression, major cardiovascular events. The more agents you can add, maybe you cannot get all 3, but you can get 2 due to insurance issues or hyperkalemia, what have you. But try to maximize these because at the end of the day, you can really make a difference in mortality as well. Really cool stuff. So encouraging.

Like I said, my nephrology colleagues are ecstatic. They want more drugs. Now they are getting greedy. It is like, why cannot we get 3 more drugs? And there are still working on more agents. So maybe in the next 5 years, we will see that.

[00;43:50]

Patient Case 3: 58-Yr-Old Man Presents to Primary Care for Annual Follow-up

Here we have a 58-year-old man, presenting to primary care for annual fall hypertension, diabetes, and CKD 3aA2 on lisinopril, amlodipine, metformin, insulin, a ton, and supplements. Blood pressure is 138/84, BMI is 34, GFR is 55, UACR-high 180, and A1C is 9.2%. So look at that drug list real fast. And let us move on to our question.

[00:44:16]

Poll 6: What medication adjustment(s) would you recommend for this patient? Please select all that apply.

Tracey Piparo: So what medication adjustments would you recommend for this patient? Select all that apply. So you could choose more than 1 answer.

1. Add a GLP-1;
2. Add an SGLT2 inhibitor;
3. Request that the patient stops herbal supplements;
4. Adjust insulin glargine dose;
5. Add cranial insulin; or
6. Increase the lisinopril dose.

Remember, you can pick more than 1 answer on this one.

Dr Vega: So our audience likes their GLP-1s. Okay, SGLT2, great. Yes, you really want those. Stopping herbal supplements could be a really good idea. And then, yes, increasing lisinopril. Yes, that is a good one.

A 33% response said increase lisinopril. The trials with ACE inhibitors and ARBs are older, but really where they were most effective was at moderate doses. Sometimes you cannot get your dose higher.

So you are stuck with a 5 or 10 mg dose, but these are not highly effective medicines at lowering blood pressure. A lot of, even my older patients can take a dose of 20 mg of lisinopril. And I feel much better about their renal chances there.

So really try to, when they have CKD, you are not necessarily, I am not necessarily using it for their blood pressure. I will titrate them at least a moderate doses, just for the renal benefits. So keep that in mind as well.

So you are good on you if you got that one too. And you can do multiple of those changes together at this visit. But that said, it is hard.

[00:46:02]

Medication Review and Reconciliation

You know, there are many factors: patient factors, polypharmacy, drug interactions, side effects that we know, side effects that are very idiosyncratic. Not only that 1 patient, a million experiences, but they are not going to take that medication because they feel they are allergic to it because, you know, the left pinky went numb for a week. And so they stopped the lisinopril and it got better. You know, I cannot explain it, but yes, then again, push the other thing.

So, going to push the GLP-1, going to push finerenone, going to push the higher-dose statin, etc. So really we are treating the patient holistically, and everybody's got a chance to do that, from myself as a PCP to the nephrologist, the cardiologist if they are seeing them, we really want to make sure that we are regularly following up with the patient and acting in a patient-centered way. So, they really have to buy into this.

[00:46:50]

Key Considerations for Treatment Monitoring

But I think 1 of the ways I do it is if they do not have a family history of kidney disease, they do not know somebody on dialysis, then that is a little bit vague for them. But I talk about how their kidney risk is exactly equate well, not exactly, but it is very much related to their cardiovascular risk that they do understand. And they are interested in preventing a heart attack, stroke, heart failure, etc. So you really want to be able to monitor patients over time.

And again, when you get an abnormal result, you are going to recheck it, but follow potassium closely. I can answer questions if you want to ask about potassium binders. The real answer there is we do not know in terms of how effective those agents are over time in terms of promoting better cardiovascular outcomes.

[00:47:30]

Shared Decision-making and Symptom Management

But it does start with the patient. And when they are invested in their care and they understand what they are taking, they are more likely to do some of those other things, go back to a plant-based diet, go back to quitting tobacco products, etc.

[00:47:42]

When to Refer to Nephrology

And so when do you refer to nephrology? Generally we refer to nephrology too late. They do not want to see patients when they are already in stage 5. Stage 4 is a good time to get them known to a nephrologist to order a baseline renal ultrasound as well. Those are generally pretty easy to get, but if they have significant metabolic complications, if any case just is not progressing as you kind of expect it to, that slow burn with diabetes and hypertension, then make their referral and then think about getting, you know, if you want extra testing, if you are worried about an autoimmune disease, test for that before sending, that way the nephrologist can act on that information, including the imaging study of the kidneys.

[00:48:21]

Advanced Care Planning

And then, really it starts with a patient for advanced care planning, but we should all be involved with that.

[00:48:27]

Multidisciplinary Care in CKD Management

Key is communication across disciplines. So they might be seeing a cardiologist and myself and, a nephrologist. They might have a social worker, and they may have mental health professionals involved or a dietician as well. That is all awesome. Pharmacy plays an important role here as well. But the key is we have to communicate. Just need to be able to, I think anyone who sees, hey, this is change, patient's not in SGLT2, why is that not happening? I am going to go ahead and prescribe it and make sure to everybody else to make it clear on the chart, make it clear on my note, and explain to the patient because they can be the best messenger in terms of what is going on in their own care, and then move forward.

[00:49:02]

Key Takeaways

So our takeaways are we really need to be screening patients with hypertension and diabetes. Hypertension now is included, UACR and eGFR.

If you get an abnormal result, the best thing to do is recheck it in 3 months and/or it could be soon highly abnormal, and you really want to make sure to stay where you can check in as early as 2 weeks. I would say as well that, unfortunately, patients are not going to present to you with symptoms that suggest chronic kidney disease. The symptoms are vague.

90% of patients have CKD and do not know it. So really it is only in that fourth stage when they get symptomatic. So that is where you want to be watching.

And then yes, the pillars of therapy: SGLT2 inhibitors, ACE inhibitors, or ARBs, GLP-1 RAs, and the non-steroidal mineralocorticoid antagonists. They look forward to better things in the future as well.

[00:49:51]

Posttest 1: Which answer correctly pairs the eGFR stage with symptoms typical of the stage?

So with that, let us get to our post-tests.

Tracey Piparo: Yes, I think they are going to do great on these, Dr Vega. Everyone's been paying attention. First question, which answer correctly pairs the eGFR stage with symptoms typical of the stage?

1. Stage G1 – fatigue;
2. Stage G2 – decreased appetite;
3. Stage G3 – shortness of breath;
4. Stage G4 – peripheral edema.

Take your time and remember to hit the "Submit" button. I think people are paying attention. We are doing pretty good on this one.

Dr Vega: Okay. Yes. This is a big improvement. Yes.

[00:50:43]

So it is peripheral edema. Yes. You are going to see your folks do not generally get symptomatic, as I said, until they are at those latest stages. So yes, you can see some symptoms earlier, but unfortunately, usually you do not. That is why we need to test proactively.

[00:51:02]

Posttest 2: Your patient has type 2 diabetes and their recent lab results reveal reduced eGFR (50 mL/min/1.73 m2 ). How would you proceed?

Tracey Piparo: Next, your patient has type 2 diabetes and their recent lab results reveal a reduced eGFR. How would you proceed?

1. Measure the UACR and provide a diagnosis of CKD if it is elevated;
2. Provide a diagnosis of CKD based on reduced eGFR in the context of type 2 diabetes;
3. Repeat the eGFR in 3 months and measure UACR for more accurate assessment; or
4. Repeat the eGFR in 3 months and provide a diagnosis of CKD if the test provides a similar result.

Dr Vega: I had 2 parts here. So think about, think about your answer.

Tracey Piparo: You had pretty good improvement on this one.

Dr Vega: Yes, that is great. Yes. So great.

[00:52:00]

Yes. Because I was afraid they would just say repeat the eGFR, but yes, if you do not have a UACR, you want to check that. So that is awesome. Good job, everybody.

Tracey Piparo: Yes. Great work, guys.

Here is another one.

[00:52:11]

Posttest 3: Your patient does not have T2D (A1C 5.5%) or overweight (BMI 24 kg/m2) but has hypertension (controlled with ACE inhibitor) and dyslipidemia (controlled with statin). Repeat measurements reveal persistently decreased eGFR (50 mL/min/1.73 m2) and elevated UACR (240 mg/g). What would you add to this patient’s treatment regimen?

Your patient does not have type 2 diabetes or overweight, but they have hypertension, which is controlled with an ACE inhibitor and dyslipidemia controlled with a statin. The repeat measurements reveal persistently decreased eGFR and an elevated UACR. What would you add to this patient's treatment regimen?

1. An angiotensin receptor blocker;
2. Metformin;
3. A non-steroidal mineralocorticoid receptor antagonist; or
4. An SGLT2 inhibitor.

Do not forget to hit "Submit" on your answers.

Equally as well on this one, Dr Vega.

Dr Vega: Yes. Yes. I am happy with it.

[00:53:09]

Yes. So SGLT2 inhibitor is the right answer here. If you said the NMRA, because they do not have diabetes, that has not been proven.

We have a feeling that the NMRA, the mineral corticoid antagonist will work in cases without diabetes as well, but that study is still ongoing. It is been proven in diabetes. So SGLT2 inhibitor is definitely the best answer here. It is also the most accessible of these different agents that will help.

[00:53:36]

Poll 7: Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

Tracey Piparo: So now we just want to know a little bit about you guys. Do you plan to make any changes in your clinical practice based on what you learned in today's program? And please be honest with us.

1. Yes;
2. No; or
3. I am still uncertain.

These answers are really important.

Tracey Piparo: Awesome.

[00:54:19]

Poll 8: Please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

One last question before we get to the Q&A section. Take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

This information is really helpful to us.

All right. So you guys are sending in some really good questions here. Are you ready, Dr Vega?

Dr Vega: Let us go.

Q&A<

Tracey Piparo: I think 1 important 1 is folks are wondering, when do you make that decision to refer a patient to nephrology from primary care?

Dr Vega: Yes. So for most patients it is that slow burn, but they are stage 4. So their GFR is now under 30. I have actually done a study of nephrologists in Canada, and that is when they said it is the right time. Maybe they are not even symptomatic, but it is the right time to send them. Maybe they are getting the exact same treatment. I feel like sometimes, but it is also good just to have the introduction. I usually, because I just find nephrology, even if I am 99% sure it is just the diabetes and hypertension over time, I will still do renal imaging when I send them just so, because a lot of nephrologists like to have that. And it is a nice chance to review the case.

Like, could there be something else going on here as well? Am I giving them a nephrotoxic drug? The biggest one of my older adults is that they have been using NSAIDs over-the-counter for years for the back pain and knee pain, etc. So really that can be a moment where it is like, yes, I am going to say nephrology. And by the way, we have to come up with some better therapy because ibuprofen 3 times a day for you is not good.

Tracey Piparo: Yes. Good stuff to think about. Another question is someone's noting that particular lab that they are using does not flag a GFR until it is below 60. Is that typical of most labs that you see? And why do you think they are waiting to flag it that low?

Dr Vega: Yes. So I think unless you are seeing a significant decline in GFR, so first of all, you are going to recheck that because many times it can also be, especially if you are talking about a GFR between it was 90 and now it is 65 in 6 months, that could be lab error as well. So it is worth rechecking that one. But in terms of actively doing something about it, most of us are not really enacting those 4 pillars until you have risk factors and the GFR below 60.

And if you do not have risk factors for the kidney, then we are going to do further investigation. Refer to nephrology.

Tracey Piparo: Okay. What type of adverse effects have you seen in patients receiving an SGLT2 inhibitor?

Dr Vega: Yes, not many. Drugs are really well-tolerated. So the thing I warn patients about are fungal infections. Usually that is more common in women, and particularly in terms of yeast vaginitis, or they can get labial yeast infections as well. These are usually treated with topical agents. The risk of UTI, I take that as a different level associated with SGLT2 inhibitors because I think it is 1 thing to have a topical fungal infection. Those very rarely progress to anything serious. They are a nuisance. They are easily treated.

UTIs, especially in severe diabetes, you can get a complicated UTI like pyelo or even bacteremia. But the relationship between SGLT2s and UTIs is actually pretty iffy. If it is there, it is a very minimal risk.

Therefore, I am not as worried. The drugs are generally well tolerated. There is a mild diuretic effect that can be bothersome for folks with detrusor instability or a history of incontinence. It usually lasts like 3 or 5 days, and then it goes away.

Tracey Piparo: I think we have time for at least 1 more question. Can you give a little bit more information, Dr Vega, on the use of finerenone, the nsMRAs, and when do you use them, and what do you hope to see in the patients when you do use them? What expectations do you have?

Dr Vega: Yes, so in my practice, and I think for a lot of other practices too, if you think about those 4 pillars, finerenone is kind of the last to go up, but I am always excited when you can complete the building and you are giving them that strong foundation. They have to have diabetes, GFR over 30, and they have to have CKD with proteinuria. That is where it has been proven in the clinical trials, again, for both cardiovascular and renal health.

The biggest limiting factor there is the potassium. Potassium is such a challenge among patients with CKD because just having CKD raise your potassium, then you have an ACR, that is going to raise your potassium, and then you are adding finerenone, which can add to their potassium as well. But there are patients who just have, you know, luckily their K is 4.8-4.9, go ahead and add the finerenone. It generally, like I said, it is not like spironolactone. It does not cause those degrees of hyperkalemia, so most patients can tolerate it, and you are going to be safe. Monitoring their GFR and their potassium every 3 or 4 months thereafter.

Tracey Piparo: Cool. I know you talked a lot about the UACR test and the utility of that. Is that expensive? Do most insurances cover it? Do you see any barriers to that being performed by someone in the primary care setting?

Dr Vega: The biggest barrier has been documented that is lack of patient insight and clinician knowledge and just getting caught up in the moment. In terms of coverage, it used to be more expensive. Now it has become so standardized that it is not expensive anymore. I think it is like a $15 test on average. I work in a safety net clinic, and I have never had difficulty getting it covered.

Tracey Piparo: That is good to know that you have not had difficulty with that.

Dr Vega: One quick caveat on that. Like I said, if you notice the level that is abnormal and you want to follow it up, you do not have to check annually. You should check again in a few months, but then you want to make sure that if you code for proteinuria, otherwise it could get flagged like, well, you already screened this patient with diabetes or hypertension. Make sure that you say why you are ordering it early.

Tracey Piparo: That is good to know because that is helpful. I think this may be our last question. It is going to be a little bit of a multi-part.

You talk a lot about using and combining multiple agents. If you had an SGLT2 inhibitor and a GLP-1, even adding in the nsMRAs. Do you observe more of a robust effect? Are the adverse effects different than if you are just using an individual agent? Are there things that folks should be looking out for?

Dr Vega: Yes. I mean, there are some combination agents out there, but there are no combination kidney agents. I feel like I can add probably 2 at a time because I would like to be efficient. Some of my patients disappear for 6 months, unfortunately, so I would want them to be protected during that time, but yes, generally well tolerated. I feel like by giving them the full year of refills and making sure that I want to see them in 3 months, but if they miss that appointment and see me in 6, I feel like they are better protected over time.