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CE / CME
Navigating the CKM Axis: Understanding the Pathophysiologic Connection Between CKD and HF
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
European Learners: 0.50 hours EBAC® effective education time
Physicians: maximum of 0.50 AMA PRA Category 1 Credit™
Nurse Practitioners/Nurses: 0.50 Nursing contact hour
Released: December 19, 2025
Expiration: December 18, 2026
Activity
Setting the Stage: The CKM Axis
Michelle Kittleson, MD, PhD:
With the excitement that silos in healthcare are intersecting more every day, the goal of this module is to discuss the shared pathophysiologic mechanisms, including the role of aldosterone, that contributes to the bidirectional relationship among CKD, HF, and metabolic disease—the CKM axis.
We will start by providing an overview of the overlapping mechanisms of CKD and HF.
Overlapping Pathophysiology of DM, CKD, and HF
Katherine R. Tuttle, MD, FASN, FACP, FNKF:
That is a big topic to cover. Let us first discuss a common form of CKD (ie, diabetic kidney disease) since CKD itself can be caused by many different diseases. What is most relevant to CKM syndrome likely is T2D because it is a driver of CKD and HF.1
Clearly, there are shared mechanisms. It has been especially fascinating for me to see the concordance, in particular between the mechanisms of CKD and heart failure with preserved ejection fraction (HFpEF). That is where I think the intersection truly revolves around disordered metabolism as a driver of inflammation and fibrosis at the tissue level.
Other organs are involved, as well. Certainly, the liver, for example, but our discussion today is more centered on the heart-kidney axis. Both organs fail because of inflammatory processes that can affect multiple cell types and compartments. The progression of inflammation then leads to fibrosis or scarring of the organs, which is ultimately what reduces organ function.2 That is the big picture on the major drivers of organ function loss and the interesting intersection between the kidney and heart.
Stefano Del Prato, MD:
T2D, CKD, and HF are becoming more common and prevalent.1,3 From an epidemiologic perspective, there is a major overlap among these diseases. As a diabetologist, I often see HF as the first manifestation of cardiovascular disease in patients with T2D. Often, this is directly associated with some impairment in kidney function. There are international data that show this, as it does not matter which region of the world you look at. That is, up to 22% of patients with diabetes have comorbid HF and 40% have comorbid CKD.2,4 So there clearly is an epidemiologic overlap.
As Dr Tuttle suggested, there also is overlap in pathophysiology. The individual components of CKM syndrome and their interrelationships are not new concepts; they have been recognized for years. Now, CKM syndrome itself is a newly defined concept that is expanding to include other risk factors and drivers of disease.5
As a diabetologist, I think that T2D is a major driving force here because approximately 40% of patients with diabetes have diabetic kidney disease.6 As mentioned, this also is a potent driver for developing HF. Therefore, I think healthcare professionals must be aware of this overlap, and treatment now needs to figure out how to break this vicious cycle.
CKM Syndrome Treatment: Band Aids vs Cures
Michelle Kittleson, MD, PhD:
These explanations are fascinating because an understanding of pathophysiology impacts clinical practice—that is, the difference between band-aids and cures.
For example, in decompensated HF, loop diuretics are a band-aid. That is because they ultimately can make neurohormonal derangements worse, but they are a necessary evil.7 The cure for HF comprises these agents that affect the RAAS and sympathetic nervous system, as well as SGLT2 inhibitors.8 It is fascinating to see how we have moved from band-aids to cures in HF.
In thinking about T2D, I remember back in the earlier days of medical school, it was taught, “treat the sugar, make the sugar better.” Now we know T2D encompasses so much more than blood sugar.
How fascinating is it that the root cause of all these conditions is unifying? The unifying root causes are inflammation, oxidative stress, endothelial dysfunction, and fibrosis, even though the organs that are affected may be different.2 The deeper you dive into your own specialty, the more you realize the commonalities you share with other specialties.
CKM Syndrome Stages
Katherine R. Tuttle, MD, FASN, FACP, FNKF:
I think you hit the nail on the head; it really is a systemic syndrome. And I think healthcare professionals must conceptualize it that way. As Dr Del Prato said, the presence of CKD markedly increases the risk of HF even among those without diabetes. But this increase in risk is especially pronounced among those with comorbid T2D.9,10 That is because there are many mechanisms by which the kidneys, like the brain, are a homeostatic controller in their own way. They ensure sympathetic neural regulation by controlling blood pressure and fluid volume.11 These are critical mechanisms that, when deranged, cause heart function to deteriorate.2
Again, I am particularly fascinated by HFpEF because it is as if the systemic milieu is really the driver of the failing heart, as opposed to more intrinsic forms of inherited or ischemic cardiomyopathy. It is an interesting intersection because that is the phenotype that really is in the middle of this systemic syndrome.12 This is not to say that patients cannot have metabolic syndrome or CKD, but HFpEF is the most adjacent condition.
The other limb is that HF clearly worsens kidney function. We can think of obvious complications like decreased blood pressure and kidney perfusion, but it is likely more complicated than that. It truly is this iterative response: the kidney gets worse, the heart gets worse, and then the kidneys get even worse.2 Then, as Dr Del Prato mentioned, it is a spiral downward to severe complications.
The Pathophysiology of CKM Syndrome
Stefano Del Prato, MD:
I appreciate the pathophysiologic background of CKM syndrome because it can provide better guidance for what we need to target in terms of treatment. If you consider the interplay between CKD and HF, again, I think we can categorize the main factors that are driving CKM syndrome. There are metabolic, hemodynamic, and inflammatory factors, among others, at play here.
We mentioned T2D is a driver but so is obesity, which is becoming a major problem. Typically, metabolic dysfunction drives these events. For example, hyperglycemia can lead to an increase in glucose flux at the mitochondrial level, which leads to the production of superoxide and oxidative stress. In addition, at the tissue level, hyperglycemia can activate the local RAAS, leading to the increase of local angiotensin II production and related detrimental downward effects.
The lipotoxicity associated with the increased availability of free fatty acid and triglycerides is another matter that can undermine the survival of critical cells in the heart and kidney.2
Then there is increased production of aldosterone due to the decreased activation of the RAAS. This affects blood pressure as well as preload and afterload, which progressively causes damage to the kidneys. With increasing aldosterone levels, fibrosis occurs in the kidneys and heart. Furthermore, elevated aldosterone levels also increase oxidative stress and inflammation, which affect the vasculature—impairing the vasorelaxation of the vessel and causing endothelial dysfunction. This then translates into another major risk that is typically seen in patients with CKD and HF: increased cardiovascular morbidity and mortality.2,10,12
I think that we now have a way to address treatment, which does act as a band-aid sometimes. But now, we have a better understanding of the pathophysiology of CKM syndrome, so drug development can attempt to hit all the different mechanisms to improve patients’ health and outcomes.
Indirect Effects of Novel CKM Syndrome Therapies
Michelle Kittleson, MD, PhD:
Dr Tuttle brought up HFpEF, which is a topic close to my heart. It is interesting to see how aldosterone antagonists were one of the first therapies that had a shared benefit across HF, regardless of ejection fraction. Then, of course, the same is being shown with SGLT2 inhibitors. It goes to show how these therapies perhaps function on a deeper level, not simply targeting the hemodynamics, diuresis, and natriuresis, but the underlying pathophysiology in CKM syndrome that leads to fibrosis.
I have always thought that the heart was the most important organ in the world. Yet I have never heard the kidneys described as eloquently as Dr Tuttlejust did. I am rethinking my life choices right now. Did I really pick the coolest organ in the world? Regardless, at least we now are all allowed to employ therapies that allow us to have this shared ability to help improve all these organs.
Thank you, Dr Del Prato for that amazing perspective on aldosterone. Dr Tuttle, can you tell us your take?
Katherine R. Tuttle, MD, FASN, FACP, FNKF:
I agree with everything Dr Del Prato said. What I could add is that the primary organ-protective effects are likely not predominantly mediated by the effect of blocking aldosterone in the cortical collecting duct—the so called “diuretic effect.” Rather, it largely may be related to the effect on inflammatory cells like macrophages and T lymphocytes that are present within the parenchyma of the kidneys and in the heart.
In the context of HF, when aldosterone binds to the mineralocorticoid receptor of those immune cells, it upregulates inflammation via a cascade of chemokines and cytokines. In the kidneys, excess aldosterone induces a profound inflammatory response, causing tubulointerstitial fibrosis and CKD progression.12
Much of the aldosterone-mediated effect may operate through immune cells that are within these tissues and that drive the inflammation and fibrosis, in addition to the metabolic effects previously described. It is a highly toxic environment for these organs. That is why there is great interest in trying to find the most effective ways to minimize aldosterone-related organ damage.
Closing Thoughts
Michelle Kittleson, MD, PhD:
As a cardiologist on this expert panel, I have learned so much. We now know about the overlapping mechanisms in CKD, HF, metabolic disease, and diabetes. There is this shared milieu of dysregulated response of inflammation, stress, endothelial dysfunction, and fibrosis.
One of the shared mechanisms, given this understanding of the pathophysiology, is the role of aldosterone in creating this process and how the inhibition of it can help. We understand now the rationale for targeting the shared pathways in CKM syndrome.
You can read the next text module in this program to learn about the importance of guideline-directed medical therapy in HF and CKD care, which applies some of this fascinating pathophysiology to the patient sitting across from you in clinic.