This post is the second of a three-part blog series. Click here to read Part 1.
Cardiovascular Disease & Chronic Kidney Disease
According to the World Health Organization (WHO), cardiovascular disease (CVD) is responsible for 31 percent of global deaths, making it a leading cause of death worldwide. This is even more significant in the Chronic Kidney Disease population where patients are up to 30 times more likely to develop CVD compared to the general population.
What’s more, patients with CKD show increased mortality due to CVD than from End-Stage Renal Disease (ESRD). This is problematic since a patient with CKD is more likely to die from CVD than progressing to ESRD, where they could be put on dialysis…a lifesaving therapy. This is substantial and very worrisome, and we really need to change that.
While patients with CKD are certainly subjected to the same CVD risk factors as the general population, they also face a host of CKD-related risk factors which compounds its impact, and helps explain the higher prevalence of heart disease, and risk of mortality, in this patient population. Some of the general risk factors are modifiable (hypertension, obesity, dyslipidemia and smoking, for example), but disease management strategies that address the CKD-related risk factors are also needed to reduce the impact on CVD morbidity and mortality.
Specifically, therapies that include targeting albuminuria, mineral and bone disease, anemia and inflammation could help reduce a CKD patient’s risk of CVD-related mortality. In addition, mineral metabolism disorders begin to develop and worsen as CKD progresses, with the kidneys’ inability to maintain calcium and phosphorous homeostasis having a negative effect on bone health and other far-reaching effects.
When kidney function drops below 60 percent (or eGFR < 60 mL/min/1.73 m2), calcium deposits begin to form in tissues and vessels throughout the body, including the coronary arteries, in a process known as metastatic calcification. These altered CKD-related coronary plaques show distinct differences from those in patients without kidney disease. In particular, the characteristics of coronary plaques in those with CKD show increased calcification, cholesterol-crystal formation and more frequent disruption, which can lead to increased risk for thrombus formation and coronary occlusion.
Biomarkers for Chronic Kidney Disease
Nuanced biomarkers capable of identifying and assessing the extent of damage in CKD are necessary to help manage the disease and delay its progression as well as the onset of comorbid conditions like CVD. Serum creatinine is one such widely utilized biomarker for kidney dysfunction.
A metabolite of muscle tissue, serum creatinine is filtered by the kidneys and acts as a measure of GFR. Multiple estimation formulas have been developed over time which use serum creatinine to evaluate kidney function, with the formulas showing utility in the management of patients in the clinic, as well as in experimental trials.
Since serum creatinine is a variable based on muscle mass and can be secreted, it is not itself the best measure of kidney dysfunction; however, it does allow for rapid acquisition and interpretation. In clinical trials as well as clinical practice, improper urine sample collection (as well as patient burden) has negated results from creatinine clearance tests to estimate kidney function, no longer making this method a gold standard.
As such, the estimation formulas were developed (and have been refined over time) to standardize the evaluation of kidney dysfunction by taking into account the variables (including age, gender, and race), that can affect serum creatinine levels.
However, even by taking differing variables into account, serum creatinine remains a poor biomarker for kidney function.
Additionally, for patients with acute kidney injury who may require dialysis, serum creatinine becomes an even less accurate predictor of kidney function as the metabolite is removed by dialysis. Since epidemiologic studies of CKD have historically used different cut-offs for serum creatinine, meaningful comparisons between results have, at times, been challenging.
In addition to optimizing accuracy, reducing patient burden must also be a key goal in biomarker selection for evaluating CKD.
Outcome Considerations for CKD Trials
Traditional clinical endpoints for nephrology trials have included serum creatinine, eGFR, proteinuria, albuminuria, kidney failure (ESRD requiring dialysis) and all-cause mortality. However, each of these endpoints have differing advantages and disadvantages, making the establishment of novel objective endpoints a key goal in CKD research.
Traditionally, a doubling of serum creatinine values has been used as an endpoint, which confers an approximate 40 to 57 percent decline in eGFR. While this is substantial, the noted demographic variables have shown this to be a less-than-perfect outcome measure.
A decline in eGFR of 30 to 40 percent has also historically been used as an endpoint; however, medicationinduced short-term changes in GFR are more likely to represent a hemodynamic effect as opposed to the overall disease stage.
The evaluation of proteinuria and albuminuria is very important in disease staging and overall prognosis, but this outcome can be complicated by the fact that a patient’s sample can be collected and evaluated in different ways: spot urine analysis or 24-hour urine collection.
Another accepted clinical endpoint for trials that evaluate CKD progression is kidney failure (requiring dialysis). For very slowly progressing disease processes, and those affecting older individuals, this endpoint can be quite impractical. This would also necessitate a long duration of follow-up, introducing the potential for some patients to die of comorbid conditions, such as CVD.
Similarly, all-cause mortality is also not an optimal primary outcome for nephrology trials because it’s not sensitive enough to identify specific causes of death related to kidney disease. This outcome is also not as generalizable to different patient populations, limiting its clinical utility.
In our final post on this topic, we’ll take a look at a case study. You can watch the webinar in its entirety here: Chronic Kidney Disease: How A Deeper Understanding of the Disease Is Impacting Clinical Development.