Activity Transcript

Luca De Nicola, MD, PhD: Hi, I am Luca De Nicola, professor of nephrology, and Director of the Nephrology Dialysis Unit and Post-Graduate School of Nephrology at the University of Campania “Luigi Vanvitelli” in Naples, Italy. And I welcome you to this program titled, Addressing the Silent Component of Your Multimorbid Patient in Primary Care: The Role of the Kidney. And joining me today is Sarah Jarvis, general practitioner, clinical consultant at Patient, visiting professor of General Practice at the University of Huddersfield in the United Kingdom, and Medical Broadcaster. Welcome, Sarah.

Sarah Jarvis, MD: Thank you. It's great to be here.

Prof De Nicola: Thank you. So, we start by saying that chronic disease, which is the focus today, is a progressive disease. You see here, all the stages, there are 5 stages of CKD. And what is important is that accurate diagnosis and staging are needed to use treatment effectively. And you can see that what is important are the middle stages from 2 to 4 to start an effective treatment. And this is because CKD is a silent disease until it becomes severe, with very poor symptomatology, few symptoms and signs. It's very important because this characteristic, this feature of CKD, is a major barrier to optimal management and, of course, treatment of these patients.

So, we can say from this slide -- this is taken from the US registry, the last annual report -- you can see how it is difficult to have a diagnosis of these patients. You see that in the last 20 years, the last 2 decades, only 12% were diagnosed with the disease, although they had disease. And this is very important because this absence of diagnosis leads to late referral to a nephrologist. In the last 20 years, there has been only a small increase in the proportion of CKD patients receiving care from nephrology on time, that being at least 1 year before they start renal replacement therapy, which includes dialysis treatment.

Dr Jarvis: And of course, this is exactly why we are here talking about the importance of primary care: because so often, what we see -- Luca don't we -- is that patients will come in, they'll be symptomatic, they'll be diagnosed on the basis of symptoms, and they will then perhaps be pushing for a referral. Also, of course, they'll be coming in to see their practitioner, and therefore, they will be diagnosed because they'll be investigated. But I think this key slide about the fact that this is a silent disease all too often means that it's very, very easy for it to be underdiagnosed and perhaps for GPs to be a little bit underaware of the importance of prevention. Now, until recently, we really haven't had a lot to offer, have we, Luca? Certainly, in the early stages, perhaps controlling hypertension and giving an ACE [inhibitor] or an ARB. That's about been as far as it goes, isn't it?

Prof De Nicola: You're perfectly right. What is important, especially for GPs, is that they are the first physician the patient sees. So, it's very important that GPs tell the patient, "Look, guy, you have CKD," because this is the only way to increase awareness of CKD in patients.

Dr Jarvis: Patients have a very low level of awareness of CKD. This is a big systematic review and meta-analysis, 32 studies. And if you look at CKD awareness among patients with CKD -- 19.2%, with an eGFR under 60 -- only a quarter of these patients who had stage 3 to 5 CKD were aware of it. Now, on the plus side, patients who were from nephrology practices were much more likely to be aware of it. But it's quite difficult, I would suggest, to be referred to a nephrologist and not realize that there is a problem with your kidneys. Even here, however, almost 15% were under a nephrologist and still didn't realize that they had CKD. But if we look at the general population -- the population who didn't necessarily have CKD, among those who did and didn't -- really scary statistics that only 1 in 12, 1 in 13 patients, that means 12 in 13 patients had no idea.

But if we now look at CKD diagnosis among patients who do have CKD, we see that actually stage 3 CKD isn't being formally diagnosed really pretty much worldwide. Even if we look at the US, which had the highest proportion of patients diagnosed, we still had two-thirds of patients with stage 3 CKD who were not being diagnosed. And that's really important because if you don't make the diagnosis of CKD, you will not have the same emphasis on preventive treatments, such as controlling blood pressure and using ACE [inhibitors] or ARB treatment, which will protect the kidneys. It will reduce intraglomerular hypertension, it will reduce progression of CKD.

And of course, we also need to remember that it's not just the kidneys. I know you're a nephrologist, Luca, but we need to remember that actually, the heart really matters too. There's a hugely high incidence, a real correlation between the incidence of CKD and the incidence of cardiovascular disease and, importantly, heart failure.

Prof De Nicola: What is important also in this study that you show is that the diagnosis rate was not different in patients with comorbidities, very important comorbidities, such as hypertension and diabetes. So, these results are more scary than they appear. And what to do? What to do is to try to improve the communication in the medical community, in the scientific community, among patient and physician. So, that's why we think that a nice approach, a very easy approach, should be synthetic and straightforward. So, this is a kind of a "4W" approach to limit the burden of CKD. We are going to answer these 4 very straightforward questions such as, “why do we need to screen?”, “who should we screen?”, “what should we screen with”, so, which test we should use to screen people for CKD, and “what should we do next?”

This is very important because it's the end of the process, the optimal treatment of patients. And let's start with the first question. First question is “why do we need to screen?” Well, this is a very easy answer if we look at the global burden of disease study, which is a huge study, a worldwide study, reporting what happened to CKD in the last 2 decades. Well, you can understand how the burden of CKD is really worrisome. We got a doubling of incidence in two decades, a doubling of prevalence, and we got a doubling of mortality due to CKD. And we have to highlight that most of the mortality rate is related to cardiovascular disease, because cardiovascular events are the major complication in chronic kidney disease.

And also, we have an increase of 62% in the disability-adjusted life years. So, we are talking about millions of patients and this is why: this is because the population is growing. This is very important for the new countries, the emerging countries, Africa, Asia. In the western world it is more caused by the epidemic of diabetes and, of course, the increase in life expectancy, because CKD is a disease typical also of the elderly.

Dr Jarvis: But it's not just the elderly anymore, is it? And I think it's really interesting. If we look at diabetes, for instance, of course the vast majority of those patients with diabetes will have type 2 diabetes. We know that, of course, ethnicity plays a role, we know that family history plays a role, but really this is to do with obesity, and particularly, abdominal obesity. And what does abdominal obesity also predispose you to? Hypertension. What's one of the other drivers of chronic kidney disease? Hypertension. So, I entirely agree that these patients are getting older, but actually a lot of my very elderly patients -- we have a very different approach to them in as much as we need to think about why we are treating the CKD, is this chronic kidney disease or is this natural age-related kidney decline?

So, an 88-year-old that I had in fairly recently who had an eGFR actually of 29, but whose eGFR had basically been drifting incredibly slowly down at about 1 milliliter per minute per 1.73 meters squared for the last 10 years. And I said, "Look, we need to protect your heart because you're at increased risk of heart failure. We need to protect your kidneys because, yes, we don't want them to drop off any further. We've got you on all the right medication actually, you are only going to reach end-stage kidney disease at this rate if you stay alive until you are 105." Very different from some of our other patients.

Prof De Nicola: Yeah, you're right, you're right, Sarah. I just want to add something because it's very important to underscore that mortality due to CKD and risk of end stage kidney disease does mean dialysis. Dialysis is independent from diabetes and hypertension. What I mean is that in the past many physicians, many colleagues, thought about CKD mortality or CKD driving people to dialysis as something was almost independent from CKD but was dependent on the primary disease like hypertension and diabetes. This legend has been forgotten after 2012 when two huge meta-analyses on over 1 million patients demonstrated that CKD has an independent role in determining the mortality and end stage kidney disease in a patient with diabetes and patient with hypertension. So what we see in terms of a prognosis of our patients is not dependent only on hypertension or diabetes, but is also determined by CKD per se by itself.

Dr Jarvis: But, of course, if we are thinking about those patients who are high risk -- in other words the, “who we should screen”-- we can turn to the KDIGO guidelines, which make it very clear the population at risk, the people that we should be thinking about. And we really do need to have a low index of suspicion. We need to be screening these patients regularly. Those with hypertension, those with diabetes, those with cardiovascular disease and those with obesity, we screen them and we screen them regularly because as KDIGO says, these are the individual- or population-level risks that will allow us to identify those patients.

Prof De Nicola: Right. And what is important is also we need to screen also older patients. I mean that the meta-analysis I was talking about, over 1 million people show that age is not saving life. I mean also in elderly, if you have CKD, the prognosis gets worse. So, we need to screen also all the people. And also, we have to think that mortality is not the natural fate of these people. Death is not the natural fate. Natural fate, the destiny of these people is to progress to end-stage kidney disease. And let's see what happened in the last 20 years in Europe. We showed the incidence over time, the last 20 years of patients on dialysis, and you can see that unfortunately, the incidence is still increasing. So, we’ve got more and more patients starting renal replacement therapy over time, also in the last years, and this is very bad.

This is very bad. Well, the tests are very easy and very, very cheap, because you can see here the heat map of KDIGO, the international guidelines in nephrology, you see the different color from green to red and, of course, people that sit in the red square are those that have the worst prognosis. And you can see that prognosis is dictated by not only GFR that you can see here on your left. So, the lower the GFR, the higher the risk. But very important is that you can see how the prognosis gets worse with increasing albuminuria. And this is very important. So, at the end, we have two easy tests to use for making an optimum screening. GFR has been measuring serum creatinine level, but maybe more important than GFR is ACR, or a simple urine examination to look at the albuminuria of the patient.

Dr Jarvis: Now I think this is really key for primary care. Because if we look at those patients we should be screening, the patients with hypertension, the patients with diabetes, the patients with obesity, the patients with cardiovascular disease, we are going to be picking up those patients who are asymptomatic. So, the patients at stage 2, stage 3a and, to an extent, at stage 3b. And I would suggest that actually, by the time you get to stage 4 CKD, well, you are in the red zone regardless of your urine ACR. And these are the patients that we should be referring, certainly at least discussing with, but usually referring to the nephrologist.

But I think the ones that are relevant for primary care are those patients with diabetes who've got a urine ACR which is raised, but actually whose eGFR may well be 75, and otherwise, if we weren't checking the UACR, we may not realize that they are at high risk. The same thing with patients who have stage 3a chronic kidney disease. Actually, if they have a normal to mildly increased UACR, their risk is very different from if they've got a severely increased UACR.

Prof De Nicola: Correct. Correct. What is important is to place the patient into this heat map, which is the basis of risk stratification for staging and prognosis.

Dr Jarvis: So, we have a couple of case studies. This is a gentleman, fairly typical patient of mine, he's got longstanding hypertension, he's already on an ACE inhibitor, and his blood pressure is pretty well controlled. So, it is within what we would consider acceptable for controlled hypertension. We've done his eGFR and his urine ACR. What we see is that he's teetering between 3a and 3b. He has an eGFR of 45 and his UACR is 2.8. So, that's really in the normal to low levels of albuminuria; that puts him in that yellow zone. And that's important, isn't it, Luca? In terms of his risk?

Prof De Nicola: Well, this is the guy who will never start dialysis. This is something which is intrinsic, inherent to physiological aging of the kidney.

Dr Jarvis: So, we still need to protect his kidneys, but we don't need to worry too much.

Prof De Nicola: But we can tell this gentleman that he will never go to dialysis, which is important. On the other hand, we can tell this guy "please don't take anti-inflammatory drugs or nephrotoxic drugs". So, this is very also important for the prognosis of the patient.

Dr Jarvis: A very helpful tip there, and something we do need to remember. What we can tell him is you'll never reach end-stage kidney disease as long as you keep taking the tablets and as long as you keep getting monitored. But our next patient, interestingly again, if we were only measuring eGFR, you might think, oh she's got a higher eGFR, what's the worry about? But actually, firstly, she's younger. Secondly, she's got type 2 diabetes. Now that is an additional risk factor, in addition to her hypertension. Thirdly, she has a very high UACR compared to our previous patient. We don't know the rate of decline of her eGFR, but I'm guessing if we had it, it would be much more rapid than our previous gentleman. But even without having that rate of decline of eGFR, even without knowing how steeply her renal function is declining, we still put her in the red zone on that heat map.

Prof De Nicola: But we can say something more. We can say that if this lady is going to be treated by an ACE inhibitor or ARB and SGLT2 [inhibitor], this lady will delay end-stage kidney disease by 15 years on average. These are some things that have been discussed and shown by RCTs like CREDENCE or DAPA-CKD. So, it is very important to identify these patients and treat them properly with the RAS inhibitors and SGLT2 inhibitors.

Dr Jarvis: So, if we think about what KDIGO recommends, we've found our high-risk patients, we've screened them, and we have made a diagnosis of CKD in a significant proportion, I suspect, if we're using the right criteria to screen. What do we do next? Well, a lot of these patients actually will be managed in primary care. Now to an extent, of course, that depends on your practice in your individual country. It depends on your availability of medication, whether you are allowed to prescribe certain medications in primary care. But there really are some fundamentals which are very much the bread and butter of primary care. And certainly, I would say that the vast majority of my patients with stage 3a CKD, I would be managing in primary care, and many of them with stage 3b CKD. Now that very much depends, I think it's fair to say, on their risk factors.

So, if we think back to our lady with an eGFR of 49, what we bear in mind is that she has an eGFR loss of more than 5 mL/min per year. So, she is at very high risk. That is the sort of patient that I wouldn't be waiting until her eGFR dropped below 30 in order to refer her or to seek advice, certainly, from my secondary care colleagues. Whereas another gentleman, perhaps who had a very, very slow decline, who had comorbidities which meant that he didn't have a life expectancy of more than a few years, whose eGFR was 29, but whose eGFR was dropping very slowly and he had low levels of albuminuria, that would be very different. I would consult with my secondary care colleagues, but I wouldn't necessarily be referring him or expecting him to be primarily managed by them.

So, Luca, I think if we look at those other patients, there are some patients where you would definitely expect to see them. The patient with hereditary kidney disease, with AKI, the patient with nephrotic proteinuria with hematuria of unknown origin, the patient with resistant hypertension, where we had confirmed that their hypertension really was resistant and it wasn't because they weren't taking their medications, and perhaps the patient with the high serum potassium, the high PTH, the high serum phosphorus. Is that fair, Luca? What are we doing with them when we get there?

Prof De Nicola: I agree. I mean, what is important is to not refer, but sharing the patients with the nephrologist because we have to share the patient, we have to share the treatment, the therapeutic goals. So, for the lady, it is clear that we need to share the patient immediately because the lady may have glomerulonephritis, so she will possibly need a kidney biopsy. For the first case report, I mean, the gentleman with the zero proteinuria, that's very much normal physiological aging of the kidney, so he can stay with his general practitioner.

But what is very important is to share also the therapeutic goals, and the first goal in these patients is to reach achieve uremia by diet and a proper dosage of diuretics. And if we correct volume expansion, we also get a normal blood pressure because most of the hypertension in our patients with CKD is dependent on volume expansion. And it's very important to reach a normal body mass index because, basically, the next epidemic after diabetes is obesity, which is associated with proteinuria, [which is] associated with faster GFR decline. So, it's very important to work together also on the body mass index and also on the lifestyle changes, Sarah.

Dr Jarvis: So, at this stage, of course, you are back on my territory, primary care territory: smoking cessation, healthy diet, regular exercise. These are the cornerstones of lifestyle advice in general practice. And, as you so rightly say, trying to reduce obesity. But actually, many of these blood pressure treatments, these pharmacological treatments, are very much primary care focus. This is our bread and butter, controlling the blood pressure, getting the HbA1c well controlled if the patient has diabetes, particularly type 2 diabetes here, which will be the majority of the patients looked after in primary care. I think most patients with type 1 [diabetes], of course, will be managed in secondary care or under a combination. Lipid management is really important because of those risks of cardiovascular disease, as well as CKD. ACE [inhibitors] and ARBs are really fundamental. Control the blood pressure, but use an ACE [inhibitor] and ARB to do it because they will independently protect the kidneys.

But so too, of course will an SGLT2 [inhibitor] within its licensed indication. Not only will the right SGLT [inhibitor] protect the kidneys in patients with and without type 2 diabetes, it will also reduce that hugely increased risk these patients have of heart failure, as well. And that is really key because it means that we are protecting across the board. The mineralocorticoid receptor antagonists, I think, are important drugs. Some of my primary care colleagues perhaps will not be quite as used to dealing with them. But if we look here, SGLT2 [inhibitors] have risen very rapidly to become foundational therapy.

Prof De Nicola: Of course. It's very important, and also, what's very important to me is the third-line therapy, because you have to figure that these drugs are not effective in all patients. So, we will still need to add therapy in patients to guarantee whole organ protection, whole body protection on heart and kidneys. So, it's very important to think about GLP-1 receptor agonists, nonsteroidal mineralocorticoid receptor antagonists. And also, don't forget to get optimal control of hypertension by adding diuretics and calcium channel blockers. And of course, good and nice and perfect control of glycemia is very important.

Dr Jarvis: Well, speaking of which, of course, KDIGO has come out with new guidance on CKD and type 2 diabetes, as has NICE in the UK. And in both of these guidelines, the SGLT2 [inhibitors] have come right up because this is where you're going to both control blood sugar at higher levels of eGFR and protect the kidneys by using SGLT2 [inhibitors]. We need to remember that the SGLT2 [inhibitors] are less effective for glycemic control as your eGFR drops, but they remain every bit as effective in terms of protecting your kidneys and, of course, protecting your heart. So, if we look at the patients who are being assessed, we've got the patients with an eGFR greater than at least 30. The high priority ones, the patients who've got heart failure, the patients who've got high levels of ACR.

We need to bear in mind the contraindications, particularly, for instance, patients at very high risk of diabetic ketoacidosis, patients who are immunosuppressed or have foot ulcers. Then, we need to consider, where do we go? So, for instance, canagliflozin, dapagliflozin, empagliflozin -- their studies and their indications vary slightly -- but we need to look at the ones which have the evidence base for both CKD and type 2 diabetes. And, of course, as we're aware, not all of them have licenses for patients without type 2 diabetes, but some do. But this is really, really important. We need to remember that we are no longer giving the SGLT2 [inhibitors] just to control glycemia, because if that was the case, we'd stop them when the eGFR dropped under 45. Now, we are giving them for a different indication.

Prof De Nicola: Yeah, right. SGLT2 [inhibitors] must be given for organ protection and I can tell you the hypoglycemia effect is a side effect of SGLT2 [inhibitors]. We need to give these drugs to protect the kidney and heart. It's very, very important.

Dr Jarvis: I think the GP in me would say that the side effect of glucose control is a very happy side effect for patients with type 2 diabetes.

Prof De Nicola: Of course.

Dr Jarvis: So, to summarize, Luca...

Prof De Nicola: Yeah, let's summarize. We have here a flow chart. Let's say, it's kind of a flow chart to take the patient from the beginning and treat them well. But here, we have the spectrum of the recommendations. But I think what I want to underline is that the first part, I mean, choose the patients that need to be screened for CKD and that is very important. It's very important. It's important exactly like the choice of the treatment. So, please don't forget the first part of this flow chart, which is the screening part.

Dr Jarvis: And I think it's fair to say all 4 of those elements are important here. You have elucidated beautifully why we need to be screening: the increase in patients reaching end-stage kidney disease, the increase in disability, but also the increase, of course, that these patients have in terms of their risk of other comorbidities, such as cardiovascular disease and heart failure. And, of course, the important thing is that if you have a patient who has CKD, that can immediately [be a] flag to you: this patient is also at high risk of these other conditions, I need to be protecting against that. Then we've got the “what do we do”? And I think, I really hope that we outline beautifully why if you use eGFR alone, then you will miss some patients who really need to be referred to you, Luca.

Prof De Nicola: Correct. Correct. Look for the proteinuria, albuminuria, urine examination, whatever you use to test for albuminuria is fine, but what is very important is to test for albuminuria.

Dr Jarvis: Absolutely. And then, if we think about what we do with them, well, that will depend on your local guidelines and perhaps your level of confidence and so on. But I think there are some fundamentals which are very much general practice focused: smoking cessation, healthy heart, exercise, weight reduction if possible, blood pressure control. But what do we control the blood pressure with? We must be using ACE inhibitors or ARBs and, really importantly, intensive control of their lipids because of their cardiovascular risk and, of course, to protect their kidneys as well, intensive control of their blood glucose. But now I think the big change that we've seen in recent years is this change. We no longer just have moderate- or high-intensity statin and RAS blockade and control of blood glucose generally. Now, we have a specific foundational therapy of SGLT2 [inhibitors], as well, for these patients with type 2 diabetes and, in some cases, for patients with CKD without type 2 diabetes.

Prof De Nicola: And I can tell you, Sarah, that SGLT2 [inhibitors] will change the natural fate, the natural history of our patients with CKD, either with diabetes or without diabetes. So, they work well in either condition and we have to think of them basically like we used to do with the ACE inhibitors in the early 1990s. Now, we have to figure that [an] ACE inhibitor or an ARB plus SGLT2 [inhibitor], this is the basic treatment for our patients, independently of the basic status.

Dr Jarvis: And that, I think, is a very fine note on which to end.

Prof De Nicola: Thank you. Thank you, Sarah. And I wish to thank all the audience for following this program. I hope that it has been interesting and innovative for you. So, thank you very much and have a nice day.

This transcript has been edited for style and clarity.