Dr. Nicholas
Welcome to episode 1 of our podcast series: Diabetes and Kidneys: Unraveling Type 2 Diabetes Silent Threat. We're your hosts, Dr. Suzanne Nicholas, and Dr. Radica Alicic.  
As we begin this series, the first thing that comes to my mind is the fact that the diagnosis of CKD, chronic kidney disease does not rely on having symptoms, because symptoms of CKD tend to develop only in the very late stages of CKD.^1,2 Therefore, the diagnosis of CKD really relies on routine screening.¹

And in fact, by the time CKD is diagnosed in patients with type 2 diabetes, they may have already had CKD for an average of seven years.^1,3,4 So early screening of those individuals who are at high risk for CKD is really important.^1-3 This is because CKD is a major complication of diabetes that significantly increases the risk of cardiovascular disease, resulting in high rates of related morbidity and mortality, and subsequently, high health care costs.^1,3,5 So today, Dr. Alicic and I will delve into some of the statistics that highlight the high prevalence of CKD and type 2 diabetes. We'll also discuss the definition of CKD, and we'll explore the crucial link between the kidneys and the cardiovascular system.

And then we'll touch on the importance of managing CKD effectively. With that, Dr. Alicic, tell us about some of the staggering statistics on the prevalence of chronic kidney disease and type 2 diabetes.

Dr. Alicic
Statistics are really staggering. In 2021, close to 12%, about 38 and a half million of Americans had diabetes.⁶ The vast majority of them, 36.4 million, had type 2 diabetes.⁶ And our podcast will concentrate on these patients. About 40% of people with type 2 diabetes will develop chronic kidney disease during their lifetime.⁷ As Dr. Nicholas pointed out, this is the disease that heavily relies on screening to allow early detection and later management of disease.^1,2  

So, what does that mean for patients? It means that their life expectancy will be shortened.⁸ Patients with chronic kidney disease have a six year less shorter life expectancy compared with people with no chronic kidney disease.⁸ If they have diabetes, they have a ten-year shorter life expectancy than those with no diabetes.⁸ But if they have both diabetes and chronic kidney disease, this effect is amplified.⁸ Not everyone is at the same risk for developing kidney disease.⁹ When we look at the data, 19.5% of non-Hispanic Black adults developed this complication, compared to 13.7 non-Hispanic Asian and Hispanic adults and 11.7 non-Hispanic white adults.⁹ So, we see the disproportionate effect on non-white adults.⁹ In addition to race and ethnicity, socioeconomical disadvantages do increase the risk of developing this disease.^10,11 

Dr. Alicic
So, Dr. Nicholas, with the understanding of this high number of cases of chronic kidney disease and diabetes, would you talk to us a little more about what is the exact definition of chronic kidney disease and diabetes?

Dr. Nicholas
Absolutely. Thank you for that question. Well, I'll start by saying that CKD, chronic kidney disease, is defined as having persistently elevated values for urine albumin to creatine ratio, or UACR, of at least 30 milligrams per gram, or an eGFR, estimated glomerular filtration rate, that's lower than 60 ml per minute per 1.73 m², or both, for at least three months.¹ And as we know, the UACR test is usually determined on an early morning urine sample.¹ The eGFR itself is determined from the serum creatinine that is put into a race-free CKD-EPI equation that includes the individual's age and sex, and then this allows us to stage chronic kidney disease across the five stages.¹ The vast majority of individuals have CKD 3 where their eGFR is between 30 and 59.¹² Kidney failure, or CKD 5 really refers to those individuals where their eGFR is lower than 151 But when we talk about CKD in individuals with type 2 diabetes, we are really specifically talking about CKD attributed to the metabolic condition of diabetes that is typically identified as a clinical diagnosis in the presence of an elevated UACR and/or reduced eGFR in the absence of any other signs or symptoms of another primary disease of the kidneys.³

Dr. Nicholas
So let me describe the typical scenario. Patients with type 2 diabetes who develop CKD usually have long standing histories of type 2 diabetes for at least ten years, elevated UACR, retinopathy, without gross hematuria, and gradually, rather than rapidly progressive loss of kidney function.^3,13  
However, it's important to note that there are some caveats to this. For example, some patients with type 2 diabetes may have CKD even in the absence of retinopathy.³
Further, while up to about 30% of patients with CKD and type two diabetes may have some level of mild hematuria, depending on the cohort that is studied,¹⁴ the presence of an active urine sediment that contains red blood cells, white blood cells, or cellular casts, as well as evidence of rapidly increasing albuminuria, particularly where there's proteinuria in the nephrotic range, greater than 3 grams of protein in a 24-hour urine sample, is nephrotic syndrome that includes nephrotic range proteinuria, as well as edema and hyperlipidemia or in patients where there is rapidly declining kidney function or severe hypertension suggest another primary kidney disease, and that patient should be referred to a nephrologist for evaluation and appropriate management.^3,15,16 Therefore, it's really important to know that patients with CKD due to type 2 diabetes can have both diabetic and nondiabetic kidney disease.¹⁷ 

Dr. Nicholas
In fact, when we look at a review of about 40 studies that examined kidney biopsies from patients with type two diabetes, the presence of diabetes related kidney disease was about 41%. On the other hand, non-diabetes related kidney disease was also about 41% and the presence of concomitant diabetes and non-diabetes related kidney disease was about 18%.¹⁷

So, with that in mind, every healthcare provider should really know the risk factors that may contribute to the development of CKD in patients with type 2 diabetes.¹⁸ And some of these risk factors include older age, particularly over age 65, female sex, it turns out that females tend to have more CKD, but males tend to have a higher prevalence of kidney failure.^8,19,20 Also, individuals from racial ethnic minority groups, particularly Black and African American individuals.¹⁹ And you heard Dr. Alicic mention that earlier. Individuals who have a family history of CKD, as well as acute kidney injury or long-standing hypertension, and obesity that may be associated with metabolic syndrome, are all important risk factors for chronic kidney disease.^19,21 The most important risk factors for CKD are diabetes and hypertension, with diabetes being the most common cause and hypertension being the second most common cause of chronic kidney disease and kidney failure in the United States.⁹

Dr. Nicholas
In fact, this type of scenario may be associated with early death from cardiovascular disease.^18,22,23 As we're going to discuss now. So, this is really a good place for us to discuss the link that exists between the kidneys and the cardiovascular system. So let me turn to my colleague, Dr. Alicic. What are your thoughts about the link between these two systems?

Dr. Alicic
Thank you for that question. That is an increasingly important questions in a time of global pandemic of obesity and diabetes.²⁴ We know that people who have chronic kidney disease are at increased risk for cardiovascular disease.¹⁸ For instance, about 55% of all adults with cardiovascular disease also have chronic kidney disease.^25,26 On the other hand more than 50% of patients with a chronic kidney disease will die from cardiovascular disease before ever reaching end stage kidney disease and requiring dialysis.^23,27 So how are these two conditions so closely related? We know that people with chronic kidney disease and cardiovascular disease share a number of risk factors.²⁸ Some of these risk factors are traditional, such as high blood pressure, smoking. Many of them will have dyslipidemia, diabetes, prediabetes.^28-30 Also, patients with chronic kidney disease have some nontraditional risk factors, such as anemia, albumin in the urine, and their calcium phosphate metabolism is abnormal.²⁸ And these risk factors interfere with all vasculatures in both organs.^31,32 Because of this connection and interconnectivity of risk factors, American Heart Association defined the syndrome, cardiovascular kidney metabolic syndrome.³³ They invited experts from different areas of medicine, endocrinologist, cardiologist, nephrologist, pharmacist, and they helped define the syndrome and with different stages and different approaches and treatments.³³ 

Dr. Alicic
We will talk more about this in episode 3 with Dr. Andrew James Sauer. So, Dr. Nicholas, I know that we will have a segment devoted to importance of the management of chronic kidney disease in type 2, but perhaps we can at least introduce the topic now. Why is early recognition and intervention so important in these patients?

Dr. Nicholas
Yeah, this is really a vital topic. Typically, when we look at the natural history and the course of chronic kidney disease in patients with type 2 diabetes, an elevated UACR tends to appear even earlier, before there's a decline in kidney function, in eGFR.^34,35 But not all patients follow this paradigm.¹⁹ And in fact, UACR and eGFR are independent predictors of cardiovascular mortality, such that a UACR, even as low as 10 milligrams per gram with an eGFR lower than 60 mL/minute/1.73 m², are significantly associated with increased cardiovascular mortality, independent of the traditional risk factors of cardiovascular disease that you mentioned.^36,37

And so, knowing this very important relationship, it's clear that early detection and appropriate intervention are critical in slowing the progression of chronic kidney disease to prevent kidney failure, which will reduce the risk of cardiovascular disease and cardiovascular mortality.^2,27 So, we can imagine that knowing these relationships, early and appropriate management of chronic kidney disease in patients with type two diabetes can also lead to reduced healthcare costs.^2,27,38  

Well, that brings us to the end of our first episode. Thank you Dr. Alicic for a great discussion. I have learned so much, and I can’t wait to explore even more in the upcoming episodes of our podcast series: “Diabetes and Kidneys: Unraveling T2D’s Silent Threat.”

Just remember, to keep following us so you don’t miss an episode. We’ve got a lot in store for you.