Dr. Nicholas
Welcome to another episode of our podcast series, “Diabetes and Kidneys: Unraveling Type 2 Diabetes: Silent Threat.” I'm one of your hosts, Dr. Susanne Nicholas, and joining me today is Dr. Andrew Sauer, who's a cardiologist and heart failure specialist. Welcome, Dr Sauer.

Dr. Sauer
Thanks so much, Dr. Nicholas, for this invitation. I look forward to the discussion today.

Dr. Nicholas
Thank you. The topic of today's podcast will focus on issues related to disease progression, complications, comorbidities, and their impact in chronic kidney disease associated with type 2 diabetes. We'll also examine the economic and societal burden of late-stage chronic kidney disease in individuals with type 2 diabetes. And as you and the audience may know, several cohort studies have shown now that the risks for progressive chronic kidney disease, cardiovascular events, and cardiovascular mortality all increase with advancing CKD stages, marked by either worsening albuminuria or worsening kidney function, defined by estimated glomerular filtration rate or eGFR.^1,2 And in addition, CKD can progress to end-stage kidney disease, requiring kidney replacement therapy in the form of either dialysis or kidney transplantation.^3,4 Further, it's important to note that CKD associated with type 2 diabetes, is a leading cause of end-stage kidney disease worldwide.⁵ Let's begin with discussing the results of some relevant studies that have looked at CKD progression and how it may lead to cardiovascular complications in patients with type 2 diabetes. I'd like to invite Dr. Sauer to give us some details about some of these important and very significant studies. Dr. Sauer?

Dr. Sauer
Thanks again for the question. I think it's important to begin with an assembly around the language that we use to talk about patients with chronic kidney disease as it relates to cardiovascular events. This is something I had to learn to familiarize myself as I began taking care of patients with cardiometabolic and kidney disease. When we think about chronic kidney disease, we don't just talk about the eGFR, as you point out, stages G1 to G5, but we also talk about UACR, A1, A2, and A3, particularly at those stages with UACR being less than 30 mg/g for A1.¹ For patients with a UACR of 30 to 299 mg/g, that's A2 or microalbuminuria.⁴ And for patients with a UACR of 300 plus mg/g, that's considered macroalbuminuria or A3.⁴ When we look at the burden of evidence that we have, a number of cohort studies, meta-analysis, for example, looking at UACR measurements, the adjusted relative risk for cardiovascular mortality, kidney failure, acute kidney injury, and chronic kidney disease progression increased across all [e]GFR categories as long as the albuminuria level was greater than 30 mg/g.⁶ In the Cardiovascular Health Study of about 1,300 adults with chronic kidney disease, stages 3 through 5, with or without type 2 diabetes, patients were six times more likely to die from cardiovascular-related causes than to progress to end-stage kidney disease.⁷

In retrospective cohort data involving 2.2 million patients with diabetes, about 150,000 patients with chronic kidney disease were compared with those without chronic kidney disease.⁸ It was found that chronic kidney disease stages as looking at eGFR advanced, there was an increased risk of not only end-stage kidney disease, but also myocardial infarction, chronic heart failure, and stroke.⁸ In another observational cohort study looking at 32,000 patients with type 2 diabetes, compared to 33,000 patients without type 2 diabetes, those that had eGFR progression, those with type 2 diabetes, were more likely to progress to a higher eGFR category than compared to those that did not.⁹ And finally, in the CRIC study, which included 3,900 adults with chronic kidney disease stages 2 through 4, the cumulative incidences of heart failure, cardiovascular disease, end-stage kidney disease, and death over five years were markedly increased when we had advancing stages of eGFR, chronic kidney disease, in addition to the albuminuria stages I pointed out earlier.¹⁰ So, for example, the five-year cumulative incidence of cardiovascular disease was 4% in patients who had the G1 to G2 and A1 stage of chronic kidney disease.¹⁰ So having albuminuria less than 30 milligrams per gram, for example, but as high as 35% when you had an eGFR less than 30 and a UACR greater than 300 mg/g.^1,10  

When you looked at the five-year cumulative incidence of heart failure, it was 2% in those lower risk categories of having essentially normal eGFR and without significant albuminuria.¹⁰ But it was 7% when the albuminuria increased to the A2 category and as much as 14% when albuminuria increased to the A3 category.¹⁰ Then when you compare this to participants with really advanced chronic kidney disease with lots of albuminuria markers, heart failure incidence was actually 20%.¹⁰ 

Dr. Nicholas
So, Dr. Sauer, what you're saying is that these studies have very robustly shown the important link between chronic kidney disease progression and worse cardiovascular outcomes.^6,8,10  
Is that correct?

Dr. Sauer
Absolutely. And I think just as a personal clinical anecdote here, when I think about how I am incorporating this with my patients, we talk a lot about how I use UACR as another biomarker, if you will, to better capture the significance of the patient's overall cardiometabolic and cardiometabolic kidney disease. This really gets into the intersection of their obesity, stress blood volume expansion, hyperaldosteronism and hypertension, remodeling of the heart on echocardiogram, left atrial enlargement, atrial fibrillation, pulmonary hypertension, glycemic control, and also management of dyslipidemia. All of these comorbid conditions that we're managing have strong intersection points when thinking about chronic kidney disease and incorporating the UACR.^11-15

Dr. Nicholas
That's really great. Thank you for that. Well, now that we know more about the impact of chronic kidney disease progression in individuals with type 2 diabetes on their cardiovascular complications, let's talk about the progression of the extent of complications and the development of comorbidities when CKD diagnosis and CKD intervention occur late.  

It's important for us to note that complications of CKD can affect all organ systems.⁶ And even in the earlier stages of CKD, before CKD becomes severe, an individual already has significant risk for cardiovascular disease.⁶ You know, factors that are associated with CKD progression and increased cardiovascular risk are considered to significantly overlap.⁶ Further, patients with CKD are more likely to die from cardiovascular disease than to progress to end-stage kidney disease.¹⁵ And in fact, CKD can be considered a coronary artery disease risk equivalent to diabetes.¹⁵ This relationship clearly emphasizes the bi-directional relationship between the heart and the kidneys.^15,16 For example, heart failure impacts the development and the progression of CKD and significantly contributes to morbidity and mortality in patients with chronic kidney disease and end-stage kidney disease.¹⁵ The incidence of new onset heart failure is about 17 to 21% in patients with chronic kidney disease.¹⁶ And the development of heart failure varies depending on the stage of CKD and the modality of kidney replacement therapy.¹⁶  

Dr. Sauer, isn't it true that as the severity of CKD increases, so does the prevalence of heart failure, and also the prevalence of heart failure translates to poor health-related quality of life?^15,16 Correct?

Dr. Sauer
Yes, this is a relationship between chronic kidney disease and cardiovascular disease that is really important for our clinicians to really recognize and take note of as we think about how to care for our patients.^15,16 We know that reduced eGFR is actually known to be associated with an increased risk of cardiovascular mortality and hospitalization for patients with both preserved and reduced ejection fraction heart failure.¹⁶ But did you also know that elevated urine albumin is predictive of heart failure outcomes independent of eGFR, which includes progression to overt incident heart failure, as you mentioned earlier,^16,17 which we also know is associated with myocardial dysfunction, remodeling of the left atrium and the left ventricle, as seen on imaging studies.^12,13 Recently, the American Heart Association actually put out a presidential advisory on cardiovascular kidney metabolic or CKM syndrome, which recognizes the multi-organ dysfunction that we've been talking about here today that affects the heart, the kidney, and the metabolic health.¹¹ Within that advisory, CKM syndrome is defined as a systemic disorder characterized by pathophysiologic interactions among metabolic risk factors, chronic kidney disease, and also intersecting, importantly, with the cardiovascular system and leading to multi-organ dysfunction with a significant increased rate of adverse cardiovascular events.¹¹

Dr. Sauer
CKM syndrome includes both individuals at risk for cardiovascular disease due to the presence of these metabolic risk factors, as well as chronic [kidney] disease or both, and individuals with existing cardiovascular disease that's potentially related to or complicates metabolic risk factors or chronic kidney disease.¹¹ CKM syndrome does have a number of effects on vascular integrity, which has both cardiovascular and renal implications, atherogenesis, which has implications for dyslipidemia, potentiating nephropathy as well, myocardial function and dysfunction, hemostasis, so bleeding and clotting disorders, as well as cardiac function.^6,11,18-20 Again, we've mentioned the markers on remodeling that we can see by imaging studies.^12,13 Really, as a result, CKM syndrome is clearly linked to a greater likelihood of all phenotypes of cardiovascular disease, which importantly include coronary heart disease, stroke, heart failure, peripheral artery disease, atrial fibrillation, and sudden cardiac death.¹¹  

Dr. Nicholas
Yes, this is an interesting new concept that provides a picture of how these systems interact and lead to severe clinical outcomes.¹¹ In fact, there are indeed other complications that may arise as chronic kidney disease in patients with type 2 diabetes progresses.⁶ For example, as eGFR declines in patients with CKD, the prevalence of CKD complications, such as anemia, hypertension, vitamin D deficiency, metabolic acidosis, hyperphosphatemia, hyperparathyroidism, and metabolic bone disease all increase.⁶ Let's look at the impact of just one of these complications. Let's take anemia. When we look at anemia, this disorder, which may become evident even in the late stages of chronic kidney disease, stage 3, which is where many folks lie, can significantly contribute to the burden of symptoms and can be associated with poor outcomes.^6,21 In fact, anemia itself is a risk factor for heart failure in patients with chronic kidney disease.¹⁵ In patients with heart failure, anemia is a common complication and is independently associated with increased mortality.¹⁵ Looking at another complication in this population, let's say hypertension.⁶ Hypertension itself is not only a complication of chronic kidney disease, but hypertension is also a common cause of chronic kidney disease, and it is associated with an increased risk of chronic kidney disease progression, as well as cardiovascular morbidity and cardiovascular mortality.^2,22,23

Dr. Nicholas
Looking at elements associated with metabolic bone disease that can affect not only the bone, but also the heart and blood vessels, serum phosphate, calcium, and parathyroid hormone are all interconnected.⁶ In fact, higher serum phosphate concentrations are associated with mortality, and systematic reviews suggest that timely phosphate control may help to reduce the early clinical consequences of metabolic bone disease and chronic kidney disease.⁶ Well, now that we have reviewed the cardiovascular complications of chronic kidney disease in type 2 diabetes and the negative impact of late diagnosis and intervention, Dr. Sauer, can you tell me about how this might burden both the patient as well as the health care system?

Dr. Sauer
Yeah, we don't always do the best job in incorporating what care costs to the patient as well as to the health care system.^24,25 But it's super important for us to take these under consideration, particularly as health care becomes increasingly more expensive for everybody involved.^24,25 So, when we look at the economic impact, it's really significant as it relates to this space of chronic kidney disease and cardiovascular complications.^1,26 So, when you look at a retrospective analysis of the Truven Health MarketScan databases, around 23,000 patients with type 2 diabetes were analyzed, and they were classified based on those A1 through 3 stages I talked about earlier.^1,27 And they found that compared to patients with type 2 diabetes and normal albuminuria, patients with moderately to severely increased albuminuria experienced significantly higher rates of emergency medicine services, as well as hospitalizations and admissions, along with an increased risk of requiring, ultimately, dialysis.²⁷ If we look at another study involving 53,000 patients with chronic kidney disease, along with type 2 diabetes in the Optum Claims Data cohort, we can see that to estimate the costs associated with managing chronic kidney disease at different stages, the study looked at the costs, relatively lower at chronic kidney disease stages 1 and 2.²⁸

Dr. Sauer
But of course, the costs really skyrocketed as the disease progressed.²⁸ Dialysis, in particular, incurs the highest management cost, highlighting the financial strain that's associated with end-stage kidney disease.²⁸ Just to put this in perspective, once patients reach the need for dialysis, this results in an estimated cost of about $50,000 over four months, which of course, translates to $150,000 over a year.²⁸ For major chronic kidney disease complications, the estimates of acute cost in the first four months after an incident event were around $21,000 for a heart attack or a myocardial infarction, $21,000 for a stroke, and even more, $31,000 for an acute heart failure event.²⁸ In the Care First National Kidney Foundation quality improvement study, which tested the impact of chronic kidney disease intervention in a primary setting and analyzed the results in about 7,400 patients at risk of chronic kidney disease with diabetes and/or hypertension, they found that as albuminuria increased, the cost for chronic kidney disease care multiplied.²⁹ In the study, there were increases in expenditures for medical per member per month as albuminuria stages increased.²⁹ For example, in patients With A1 stage albuminuria less than 30 mg/g, the cost was $592. But in patients who had A2 stage, so albuminuria from 30 to 299 mg/g, the cost went up to over $1,000 per member per month.²⁹

Dr. Sauer
And in patients with more advanced albuminuria, stage A3, greater than 300 mg/g, the cost per member per month was about $1,800 a month.²⁹ So, you can see how this assessment of UACR tracks with the economic burden.²⁹ And in a retrospective cross-sectional study of about 35,000 adults with diabetes identified from the Medicare Expenditure Panel survey and their annual medical expenditures being analyzed, after adjusting for a number of covariates, patients with chronic kidney disease associated with diabetes had about $12,000 higher total direct medical expenditure when compared to patients with diabetes, but without chronic kidney disease.³⁰ We know that cardiovascular disease increased the medical expenditures by about $8,000 in patients with chronic kidney disease associated with diabetes when compared to those with diabetes but without chronic kidney disease.³⁰

Dr. Nicholas
Indeed. These studies offer truly valuable insights into the economic implications that are associated with CKD in patients with type 2 diabetes.^28-30 It's clear that proactive management strategies and targeted interventions are crucial in alleviating the burden on both the patient as well as the health care system.^25,31 With that, I'd like to thank you, Dr. Sauer, for providing us with your amazing insights today, and to invite our audience to join us for the next podcast episode. Thank you.