What are the nuts and bolts of diabetic nephropathy diagnosis and treatment?

In this episode, Kidney Essentials hosts Drs. Sophia Ambruso and Judy Blaine along with guest-host Dr. Jake Hershey discuss the diagnosis and treatment of diabetic nephropathy and some of the nuances of our favorite RAAS inhibition medications.

Sophia Ambruso DO @Sophia_Kidney, Sarah Young MD @kidneycritic, Judy Blaine MD, Parisa Mortaji, MD

Transcript

Kidney Essentials

Season 2 Podcast episode #1

TITLE: What are the nuts and bolts to diabetic nephropathy diagnosis and treatment?

Welcome to Kidney Essentials!

This is A Podcast for Medical students, residents and all nephrocurious practitioners at the University of Colorado and beyond. We’re here to make nephrology more accessible one podcast at a time. JUDY: “ and sexy!”

We have a special guest with us today, one of our talented 2nd year internal med residents at the University of Colorado. Jake, please introduce yourself!

Jake: (name, affiliation, COI and twitter handle)

We are missing sarah today as she is out and about enjoying the end of the summer! Judy, why don’t you say hello…

Judy: (list name, affiliation, COI and twitter handle)This podcast is for educational purposes only. The views and statements expressed on this podcast are soley those of the hosts.  This podcast should not be used as medical advice or for treatment purposes

And I’m your host for tonight; Sophie (list name, affiliation COI and twitter handle)

Sophie: Ok gang, last podcast on diabetes to round it all out!! Today, we’re going to touch a little bit more on diagnosis, indications for biopsy and some of the nuances of treatment. Let’s go back to our case as a reminder…

You are consulted on a 45 YO woman with poorly controlled type I diabetes mellitus complicated by diabetic neuropathy, hypertension with worsening proteinuria and GFR. Patient has 800mg/g of albuminuria, 1600mg/g of proteinuria and bland urinary dipstick. Upon meeting the patient, she reports recently being diagnosed with diabetic retinopathy.

So, from our previous 2-3 podcasts, we established that this patient has a clinical diagnosis of diabetic nephropathy. Judy, what is the significance of her diabetic retinopathy diagnosis?

Judy: Diabetic retinopathy is present in nearly 100% of patients with type I diabetes and diabetic nephropathy. The presence of diabetic retinopathy is part of the criterion for clinical diagnosis of diabetic nephropathy  in patients with type I diabetes. The same is not true in type II diabetes where only 50-60% of patients exhibit retinopathy.

Sophie: which brings me to my next question, Jake, what are the clinical diagnostic criteria for diabetic nephropathy??

Jake: you can rewrite this to make it sounds more conversational if you like.

 Sophie: So Judy, Jake said hematuria can occur in 10-15% of patients with diabetic nephropathy, how can that be?Judy: some discussion of glomerular injury in DN. 

Sophie: Just to come full circle, remember we spent a large portion of last podcast on hyperfiltration being an early feature of diabetic nephropathy, which typically manifests as enlarged kidneys, which is part of the diagnostic criteria of diabetic nephroparhy. As a caveat, in more advanced cases of diabetic kidney disease, kidneys may be small and scarred.

Sophie:Judy, is there any indication to biopsy this patient?Judy: no, as mentioned before, this patient is fairly straight forward, has progressive albuminuria and CKD and diabetic retinopathy. She has no additional features that I would suspect an alternative diagnosis that would warrant biopsy.

Sophie: Jake, for our listeners, would you summarize the indications for kidney biopsy in a patient with diabetic mellitus and kidney dysfunction?

Jake: you can rewrite this to be more conversational if you like. 

Sophie: summary statement

Sophie: Let’s move on to treatment, what are the goals of diabetic kidney disease management? And how would you treat our patient?

Judy: all of this in your own words.

Before thinking about pharmacologic intervention, we must also address the modifiable risk factors for DKD progression; glycemic control (A1c goal <7%), improved blood pressure control (goal <130/90) and encourage and facilitate smoking cessation and weight loss while simultaneously starting and maximizing, as tolerated, medicines that aim to preserve glomerular hemodynamics through the reduction of intraglomerular pressures; these include ACE inhibitors, ARBs, and the new SGLT-2 inhibitors. 

Sophie: Jake, we spent a lot of time on this on our last podcast but will you review how RAAS inhibition is helpful in treating DN?

Jake: (again, feel free to rewrite this section so it sounds like ‘you’) RAAS inhibition reduces afferent arteriolar vasodilation and efferent vasoconstriction, thereby decreasing intraglomerular pressures and hyperfiltration to prevent albuminuria, progression of albuminuria, progression of DKD and development of ESKD in patients with DKD.

 Sophie: It sounds like we should keep RAAS inhibition going in our patients with diabetic nephropathy at all costs. Jake, what advice do you have for our patient’s PCP when she calls you about a decline in eGFR and serum potassium of 5.1 while on her RAASi?

Jake: In general, we try to continue aggressive RAAS inhibition as long as GFR remains ≥20ml/min. We tend to tolerate a drop in GFR as long as it does not exceed a 30-35% decrease and stabilizes within the first 2-4 months of drug initiation or uptitration. 

Judy: For hyperkalemia, we will try to continue RAAS inhibition while modifying dietary potassium intake. If hyperkalemia persists despite dietary modification, one of the novel gastrointestinal potassium binders like sodium zirconium cyclosilicate (Lokelma) or patiromer (Veltassa) is recommended while continuing maximum tolerated doses of RAAS inhibition.

Sophie: Let’s talk about SGLT-2i, what is the mechanism of action of SGLT-2 inhibitors and how are they renoprotective?

Judy: SGLT-2 inhibitors block the sodium glucose co-transporter 2 in the proximal kidney causing sodium to remain in the lumen, leading to a robust natriuresis, reducing intravascular volume and blood pressure. Additionally, increased sodium delivery to the distal kidney and macula densa occurs, which downregulaties TGF and RAAS activity, thus decreasing afferent arteriole vasodilation with a resultant reduction of intraglomerular pressures and preservation of glomerular hemodynamics. 

Sophie: We’ve heard quite a bit about SGLT-2 inhibitors, what’s the big deal anyways??

Jake: By the mechanisms Judy just mentioned, SGLT-2 inhibitors reduce the degree of albuminuria and risk of DKD progression, independent of glycemic effects, lower the risk of ESKD development or kidney disease associated death, independent of baseline albumin secretion or RAAS inhibition. Finally, SGLT-2 inhibitors reduce the rate of major cardiovascular events, hospitalizations and death in individuals with atherosclerotic disease regardless of diabetic kidney disease. 

Sophie: Judy, your patient is asking about potential side effects, how do you counsel a patient when starting them on SGLT-2 inhibitors?

 Judy: some of this is debatable as it depends on which trial you look at but we currently counsel our patients about the following potential risks; Glycosuria and volume depletion due to diuresis, urogenital infections, typically vulvovaginal candidiasis, have been reported to be increased by 2 to 4-fold, fournier’s gangrene (rare), euglycemic diabetic ketoacidosis requiring appropriate dietary counseling prior to initiating. In early trials, there appeared to be an increased risk of lower limb amputations associated with use of the SGLT-2 inhibitor, canagliflozin, however, this was not observed in subsequent trials. 

Sophie: Right, in the DAPA-CKD trial published in NEJM of 2020, there was no statistically significant difference in severe adverse events between those on Dapagliflozin versus placebo. In particular, no signal for increased risk of amputation, diabetic ketoacidosis or fourneir’s was identified.

Sophie: So, who are candidates for SGLT-2 inhibitors?

Jake:

Inclusion criteria:

With or without DM II (no DM I)

No DM, GFR >25-60 ml/min/1.73m2 OR ACR >30mg/g AND/OR and albuminuria

Established cardiovascular disease like CAD, HF, CVA

Exclusion criteria:

H/o recurrent UTIs, chronic in dwelling catheter, requirement for self-catheterization.

Inability to maintain good genitourinary hygiene

Significant peripheral vascular disease identified on exam

Sophie: Judy, you again get called about eGFR decline by your patient’s PCP after starting an SGLT2i, how do we interpret the drop in GFR after initiating SLGT-2 inhibitors?

Judy: It’s true we’ll often see a GFR drop similar to that seen with the initiation of RAASi, which is an anticipated physiologic consequence of SGLT-2 inhibition but there is no evidence of acute kidney injury. We can expect an approximate 10% eGFR decline, which is followed by stabilization of GFR.

Key Points

1. Diabetic nephropathy is a usually a clinical diagnosis, consider biopsy when the presentation deviates from classic findings

2. Attempt to aggressively treat modifiable risk factors like glycemic control, blood pressure, weight loss and smoking cessation

3. RAAS inhibitors (ACEi/ARB) and SGLT-2 inhibitors are considered renoprotective agents through the preservation of glomerular hemodynamics.

4. In patients with albuminuric DKD, attempts to maximize and continue ACEi or ARB therapy should be made including low potassium diets and K binders like sodium zirconium cyclosilicate (Lokelma & Veltessa).

5. In select patient populations, SGLT-2 inhibitors should be initiated and maximized.

Josh strong for graphics

And of course the University of Colorado division of RENAL disease and HTN  for giving us our jobs!