Dr. Nicholas
Hello everyone, and welcome back to “Diabetes and Kidneys: Unraveling T2D’s Silent Threat.”  
I'm Dr. Susanne Nicholas, and I'm here with my colleague, Dr. Radica Alicic.
In this episode, we'll discuss the importance of screening and diagnosis of chronic kidney disease, or CKD, in patients with type 2 diabetes. In particular, we'll describe specific screening tests using the urine to measure the albumin-to-creatinine ratio, or the UACR and the estimated glomerular filtration rate, or eGFR, from a blood test.^1,2
We'll talk about the risk factors for CKD in patients with type 2 diabetes, especially because of the lack of symptoms in these patients.¹ And we'll examine how screening can be implemented in routine clinical practices.
In our previous episode, we talked about understanding CKD associated with type 2 diabetes, and we reviewed facts around the high prevalence of CKD and type 2 diabetes.^3,4 We highlighted the crucial link between the renal and cardiovascular systems. And if you were not able to join us for that first episode, please go back and take a listen.

So, let's get started. So let me turn to Dr. Alicic to discuss the first topic. Dr. Alicic, what do you think patients should know about screening for CKD associated with type 2 diabetes? 

Dr. Alicic
Dr. Nicholas, that is an excellent question. In contrast to many other conditions, such as COPD, when patients come with a shortness of breath, or coronary artery disease, when patients come with chest pain, early stages of chronic kidney disease are asymptomatic.^1,5-7 Therefore, routine screening is crucial for detection and diagnosis of CKD.²
It is also important to point out that it is necessary to check both urine albumin-to-creatinine ratio, or UACR and estimated glomerular filtration rate, or eGFR.^1,2  

Dr. Nicholas, perhaps you could point out the reasons that underscore the significance of examining both biomarkers. 

Dr. Nicholas
Absolutely. First of all, I want to remind everyone that an elevated UACR, that's 30 milligrams per gram or greater, indicates that there's some degree of kidney damage that's going on.^1,2 While the eGFR tells us more about the level of kidney function, with the eGFR of 90 mL/min/1.73 m² or greater representing normal kidney function, and an eGFR lower than 60 mL/min/1.73 m² represents reduced kidney function.^1,2
The best way to really understand why both of these biomarkers are needed, when we're assessing an individual's risk of CKD progression, is to look at the KDIGO heat map.² And KDIGO stands for the Kidney Disease Improving Global Outcomes and the heat map, as you know, is a color coded chart that allows us to not only stage chronic kidney disease, but by including both the eGFR and the UACR, we can identify an individual's risk of progressing to a more severe stage of chronic kidney disease.²  

Dr. Alicic
I could not agree more with you on importance of KDIGO heat map. So, I think that KDIGO heat map is a very useful and very important tool that helps not only experts; but, allows patients to visualize their risk for progression of kidney disease.^2,8 In my experience, knowledge is power and helps with patient engagement and conversations about potential lifestyle changes, adjustments, and treatment options.^1,2  

Dr. Nicholas
Yes, it certainly can be used as a tool to initiate the conversation around lifestyle changes, and it allows both the provider and the patient to monitor the results of these lifestyle changes, as well as the impact of those changes, and as a guide for appropriate and early interventions that would slow down the progression of kidney disease.^2,8 Well, let's now turn to appropriate timing for screening and making the diagnosis of CKD in patients with type 2 diabetes.

So, Dr. Alicic, can you provide us with some comments on the importance of screening and diagnosis for CKD in patients with type 2 diabetes?

Dr. Alicic
Surely, Dr. Nicholas. So first, I want to thank you for explaining why we need to check both UACR and eGFR.² It's always easier to follow recommendations if we understand reasoning behind them.⁹ The question is when to start screening and how frequently to do it.
So, all major professional societies, including American Diabetes Association, KDIGO, you already mentioned, and American Association of Clinical Endocrinology, recommend annually screening for chronic kidney disease starting at the time of diagnosis of type 2 diabetes.^2,10
The reason for this recommendation is that metabolic abnormalities that are typical of type 2 diabetes are present for a number of years prior to making exact diagnosis.^2,11  

If patient is not diagnosed with chronic kidney disease, we need to continue to screen them annually.^2,11  

Dr. Nicholas
Correct, as you just mentioned, the preferred test for albuminuria that is recommended by these organizations is the UACR in a spot urine sample.^2,10 And although the UACR itself can be measured at any time during the day, the value from an early morning urine sample is really ideal.¹ Also, there are other methods to detect urine albumin available, for example, such as a urine dipstick.¹ But this does not allow us to account for a patient's volume status.¹ And when we look at other tests, like the 24 hours urine collection, it's somewhat inconvenient and typically, it's only necessary when the provider needs to have an accurate assessment of the total amount of protein a patient is spilling, or the provider is involved in making significant changes to the patient's medication regimen, such as in the presence of a primary kidney disease.^1,11,12 It should also be said that while the UACR is the only currently approved urinary marker for monitoring chronic kidney disease, there are a number of studies where investigators are trying to identify and to validate other biomarkers that are more sensitive and even predictive of kidney damage.^1,2,13

Dr. Alicic
Thank you for that comment, but let's talk about a screening issue and use of UACR and eGFR.
For example, I have a patient with type 2 diabetes whose UACR comes back elevated at 200 milligrams per gram and their eGFR is 60 mL/min/1.73 m².

Can I diagnose them with CKD? 

Dr. Nicholas
Not quite.
Remember, the requirements for making a diagnosis of CKD is the presence of persistent abnormalities of the kidneys, either from imaging studies or from laboratory results, for at least 90 days.² So for your patient, you'd need to repeat the tests within three to six months to confirm the diagnosis of chronic kidney disease.¹ Because depending on the patient's condition, both the UACR and the eGFR can fluctuate.¹ So clinically, the UACR and the eGFR can help us with the diagnosis of CKD in patients with type 2 diabetes to make a diagnosis of what we call diabetic kidney disease.¹¹ But it is a kidney biopsy that is actually the gold standard for a diagnosis of diabetes specific kidney disease or diabetic nephropathy.^14,15      

Dr. Alicic
In six months, my patient comes back and their UACR is still moderately increased at 230 milligrams per gram, and their eGFR is now 60 mL per minute. Because changes are present for more than 90 days, according to guidelines from professional societies, I can make a diagnosis of CKD, and this is a very good example on how to benefit from use of KDIGO heat map.^2,10
It helps in initial discussion with patient because it demonstrates CKD stage and helps visualize their risk of progression of kidney disease.²  

For instance, my patient is in G2A2 category, putting them at moderate risk for progression.²  

Furthermore, KDIGO heatmap helps me guide monitoring, determine frequency of visits, treatment, and need for referral to you or one of your colleagues.²   

Dr. Nicholas
Absolutely. So, for those patients who already have chronic kidney disease, as you've identified with your patient, monitoring their UACR and eGFR, let's say one to four times per year, is recommended, of course, it depends on the stage of their chronic kidney disease.^2,11 So, with your patient, annual checks of UACR and eGFR should be fine.² However, once the eGFR starts to fall below 60, or the UACR increases above 30, and in this case, the UACR has remained very elevated, you may need to have more frequent monitoring, and you want to start to think about referring to a nephrologist such as myself, particularly if the eGFR starts to decline very rapidly and the UACR makes significant increases.^1,2
So, there are other indicators for referring a patient to a nephrologist, and they may include things such as the patient achieves nephrotic range level of proteinuria, or they develop gross hematuria, or their blood pressure becomes too difficult to control.^1,11  

Dr. Alicic
Excellent. Thank you so much for that clarification. Okay, so apart from albuminuria and eGFR, we should not forget that we need to address other risk factors for progression of chronic kidney disease and diabetes, such as uncontrolled diabetes, so we have to improve control of hyperglycemia in these patients, hypertension, hyperlipidemia, and also talk about dietary patterns and weight management.^2,16,17
Anything else you would like to add to this, Dr. Nicholas? 

Dr. Nicholas
Yes, indeed.
Both traditional and nontraditional cardiovascular risk factors might exist in these patients.¹⁸      
So, it's important to have a comprehensive approach to assessing how they are in terms of understanding chronic kidney disease, and this then enhances our ability to assess their cardiovascular risk.^2,11  

So, let's talk now about the importance of screening and diagnosis. 

Dr. Alicic
Okay, so we just stressed how important is to detect elevated albuminuria or low eGFR by screening.
Unfortunately, it looks like studies are demonstrating that we are not doing very good job checking either of these biomarkers, or especially both of these biomarkers.^19,20
Is that correct? 

Dr. Nicholas
Exactly correct. In fact, there's one study where they looked at over 500,000 patients with type 2 diabetes, and they assessed the rate of UACR testing as well as the rate of eGFR testing.¹⁹
And at one year, the testing rate for UACR was 53%, and the testing rate for eGFR was actually as high as 90%.¹⁹
But when you looked at the testing rate for both the UACR and the eGFR, it was as low as about 50%.¹⁹ So, these numbers clearly indicate that there's room for improvement.

So, Dr. Alicic, knowing this type of data, are both eGFR and UACR actually available for you to order in your electronic health record system when you're trying to screen for chronic kidney disease? 

Dr. Alicic
Wow, so now that is a tricky question. eGFR is calculated from creatinine, which is easy and typical blood test we order basic metabolic panel, or CMP, on our patients.⁸ However, checking albumin is a little trickier because the patient needs to come back day after, so we can check their first urine albumin sample, so some of patients don't come back honestly.¹ So, do you have advice on how to improve rates of screening?

Dr. Nicholas
In my own practice, the way that I try to facilitate this testing, is that I would give the patient a labelled plastic container so that they can then bring in their morning urine sample when it's more convenient for them. And that typically increases the chances that they'll come back and bring the test to the lab. But actually, the National Kidney foundation worked really hard, some years ago, with multiple laboratories across the country to make a single test available, and it's called the kidney profile test.²¹ And this test is now available to providers across the country.²¹ It's actually a single laboratory order that combines both the UACR and the eGFR into a single test, so it makes ordering both tests much more streamlined.²¹ And it's really crucial to advocate for regular screenings and proactive health care, as up to half of all patients with type 2 diabetes may be living with undiagnosed chronic kidney disease.^7,22  

And why, you ask, is early diagnosis so crucial for patients?
Well, results from several studies, including the third NHANES study, which is a National Health and Nutrition Examination survey that's provided to non-institutionalized adults across the United States to get information about their health status, and there's also another study called the FIELD study that looked at the effect of lipid lowering on cardiovascular mortality.^23,24
These studies both showed that increased cardiovascular related death exists in patients with chronic kidney disease associated with type 2 diabetes.^23,24 But even in a separate meta-analysis, they showed that UACR above ten milligrams per gram, which, as you know, is lower than the lower limit of normal for UACR, and an eGFR below 60 mL/min/1.73 m², were each independently associated with increased risk for cardiovascular mortality.^2,25
The fact is that early detection allows for intervention opportunities to slow chronic kidney disease progression and to reduce the risk of cardiovascular events.⁷   
And with that, at we've covered the critical importance of screening and diagnosis of CKD in patients with type 2 diabetes. Remember, early detection can be a game changer.

Dr. Alicic
Thank you, Dr. Nicholas. These are very important points that we have to keep in mind.
And thanks for tuning in, take care, everyone.