Diabetic Nephropathy 2025 Review of new agents

 

Inspired by a recent talk I listened to by Dr. Marteen Taal

In the NEWS: Credence, Rise of the Nephron Throne

A positive light at the end of the tunnel for nephrology, the Credence trial just got published this week in NEJM, put the glucoretics on top for diabetic nephropathy. When you search “credence” in the oxford dictionary it means” belief in or acceptance of something as true”.  I think the time has come to believe that SGLT-2 inhibitors are here to stay and are going to change the disease of diabetic nephropathy.

In summary, this large RCT was stopped early. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m²), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group. The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34%  and the relative risk of end-stage kidney disease was lower by 32%. The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke and hospitalization for heart failure. There were no significant differences in rates of amputation or fracture.

Some of the twitter world made some amazing comments on this

Susan Quaggin‏ @SusanQuaggin" 19 years since RENAAL and IDNT..followed by a series of negative trials...but the drought is over! New therapies for our patients with diabetic kidney disease are a reality - #CREDENCE marks the beginning of a new era in Kidney Medicine "#SockItToKidneyDisease"

Juan Manuel Mejía‏ @Meyaix "Every nephrologist is now talking of #CREDENCE ."

Jennie Lin, MD MTR‏ @jenniejlin"#CREDENCE, landmark clinical trial for patients with T2DM and kidney disease, is now published: 30% lower relative risk for primary renal outcome in canagliflozin arm, with pretty darn significant p-value of 0.00001! It was thrilling to watch the results stream live from #ISNWCN!"

And my personal favorite....

Steven Coca‏ @scoca1 "You had me at “hello” before the gasp & applause for the tiny p value The separation of the KM curves (effect size) and 95% CI are what had me leaping And more fist pumping when the difference in eGFR slopes were shown"

While this drug was developed and marketed to treat diabetes, it is more than that. Someone on social media world rightly said” We have an anti HTN and renal protective med that has a nice side effect of lowering your A1c”

It decreases blood pressure

It induces weight loss

It decreases intraglomerular pressure

It is a proximal tubular diuretic

It is anti-inflammation

It decreases proteinuria

This is a nephrologist's drug! Finally, we have a positive trial in the making that is going to change the practice of nephrology. Diabetics, non-diabetics, HTN, CHF patients- all might benefit from this discovery!

 

Topic Discussion: SGLT-2 Inhibitors: An update

The glucoretics SGLT-2 inhibitors have really come with a wave to improve the outcomes in diabetic patients, especially cardio-vascular and renal outcomes. I had the pleasure to listen to Inzucchi SE recently on this topic and the science has really taken off.

Here is a summary of what is happening in the world of SGLT-2 inhibitors and what we need to know as nephrologists.

SLGT-2 inhibitors overall(  all of them) only have a minor to modest effect on A1C reduction. For anything, it might even stay the same after 12 weeks on the drug. This doesn’t translate into the benefits we see in trials. Regardless of the A1C being only modestly decreased, the cardiac benefits are amazing.

Even though they have a weight loss effect( usually just 2kg total no matter what), they are not approved for weight loss

Even though they have a significant bp effect, not approved for BP management

Obviously, they are not going to work if you have no URINE, so unclear benefit in ESRD patients

All trials, from CANVAS to EMPA-REG(empagliflozin), the cardiovascular benefits have been astounding- decreased number of MACE events( MI, stroke, cardiac event).

What the cardiologist world is excited about is also the decreased CHF admissions and readmissions ( perhaps due to the naturetic effect of the agent acting as a proximal tubule diuretic without really increasing renin-aldo axis)—making it an amazing drug for volume management. Recent studies have also shown increase in HCT with the drug use showing it’s effect on plasma volume.  Ongoing trials might shed light on CHF management in diabetics and non-diabetics with this agent. A recent review summarizes this.

Renal outcomes in EMPA-REG, initial decrease in GFR was reversible – related to the hyperfiltration decrease( similar to ACEI/ARB). But hard renal outcomes, 46% decrease in  doubling of crt, RRT or renal death. In addition, decrease in macro and micro-albuminuria as well.

CANVAS study- with a different drug- also similar MACE outcomes as EMPA-REG, but component of MACE individual were less pronounced. Comparable CHF benefits. Canaglifozin related CANVAS had more amputations and fractures as a major side effect that EMPA-REG(empagliflozin) data didn’t show that when re done to look for it; unclear why one drug does it and other doesn’t.  Visual abstract from NephJC

CANVAS Renal outcomes…40% reduction with agent with change in EGFR, dialysis and death-almost similar.

Should we start using this drug in diabetic patients with CKD? Or even CKD patients without DMII given significant cardio-vascular and renal benefit. When cost analysis was done, empagliflozin use resulted in higher total lifetime treatment costs ($371,450 versus $272,966) but yielded greater QALYs (10.712 vs. 9.419) compared to standard treatment. This corresponded to an ICER of $76,167 per QALY gained. This suggested that empagliflozin would be cost-effective in 96% of 10,000 iterations assuming a willingness-to-pay threshold of $100,000 per QALY gained.

Here is a nice review on both drugs and effects.

If we start prescribing as nephrologists, likely will be empagliflozin and dose of 10mg given similar effect and monitor for what effects? As might not change A1C anyway—more long term benefits such as cardio-vascular and renal effects.

We truly have entered a new era!!

Nephrology Crosswords: Diabetic Nephropathy

Check out the next installments of our crosswords in Kidney International on Diabetic Nephropathy

Topic Discussion: Metformin and CKD

The package insert of Metformin says

“Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels 2 I .5 mg/dL [males], 2 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS). “

This is dated back when this drug was introduced decades ago.  Most physicians withhold this very useful agent in most patients with a crt >1.4mg/dl.  But cautious use have been tried by many in advanced CKD and there are not many cases of lactic acidosis. 

This well done study in JAMA by Inzucchi et al reviewed over 800 publications on this topic of CKD and use of metformin from 1950 and 2014 and looked at major studies, case series and retrospective data.

What did they find?

1.       Lactate level was normal in patients with GFR of 60-90ml/min and even in patients with GFR of 30-60ml/min

2.       Most cases of lactic acidosis occurred in setting of a “second hit”- such as volume depletion, sepsis, AKI. Etc

3.       The rate of lactic acidosis in patients taking metformin was same as lactic acidosis in patients not taking metformin

4.       What did they recommend: 

Not to initiate metformin in patients with GFR< 45cc/min
Contraindicated in patients with GFR <30cc/min

5.       They recommended max doses based on GFR:

If GFR >60- max dose 2550mg per day

If GFR 45-59- max dose 2000mg per day

If GFR 30-44- max dose of 1000mg per day

Maybe it’s time we liberalize our guidelines to use metformin in CKD. Look what the Australians and Canadians are doing.  

Diabetic Kidney Disease: Old and New View

A recent article by Dr Sally Marshall in ACKD reviews the natural history of CKD in diabetic patients and reviews the old and the new view of looking at Diabetic Nephropathy. Highly recommend this article for everyone to review.  Here is a short summary of the review.

Old view:

Microalbuminuria is permanent and progresses to proteinuria in most cases.
The peak incidence of DN is 16 years and few after 35 years>
Classically, the microalbumuria progresses to proteinuria and then GFR declines
Usually, this was an older individual disease.

New view:

Low levels of albuminuria( rather than microalbuminuria) is a reversible phenomenon in majority( likely representing more of a hemodynamic change, inflammatory change or endothelial injury rather than structural damage in the kidney)

Higher levels of albuminuria are more likely to progress to proteinuria.
Peak incidence of diseases now ranging from 16-30 years
Atypical forms of presentations are becoming common where GFR decline can be seen without any prior proteinuric variant.  A vigilant watch is needed to notice this “non classical” DN
Finally, young adults are being effected with this entity and CKD become more of a common disease in Type 2 DM at an earlier age.

TOPIC DISCUSSION: Mechanism of Proteinuria in Diabetic Kidney Disease

What is the mechanism behind this entity that we see so frequently?

If we look at it from different sites of injury, there is data to support each one of these theories.

 Proximal Tubule injury:  leading to decreased protein reabsorption leading to proteinuria.

Hemodynamic injury: leading to glomerular hyperfiltration leading to increase glomerular pressure and proteinuria

Mesangial cell injury: leads to hypertrophy, matrix expansion, and mesangiolysis leading to glomerular hypefiltration and proteinuria

Endothelial cell injury: leading to altered VEGF leading to podocyte damage

GBM injury: leading to decreased negative charge and proteinuria

Podocyte injury: leading to podocytopenia or foot process effacement and leading to apoptosis, degradation or lack of proliferation.

Vascular insult:- leads to ischemia that can lead to tubular injury leading to proteinuria.

Which one is primary and which is secondary mechanism?  Can diabetic disease progress without albuminuria? Yes it can.

Current literature supports that diabetic kidney disease is mainly due to glomerular filtration barrier changes, changes in endothelial damage and GBM and direct injury to podocytes, Mesangial involvement is more of secondary role.   Tubular interstitial damage is also playing a role but it the former factors that if disrupted lead to ongoing proteinuria.  This explains why when we have accelerated HTN on top of diabetic nephropathy, there is increase in proteinuria likely due to increasing glomerular endothelial damage.

A nice review on this topic can be found in an article in KIfrom 2008.

Topic Discussion: Diabetic Nephropathy Pathology Classification

As we all know that if there is a clinical history of DMII in someone with proteinuria or renal disease,   DM nephropathy is always on the differential on what one might find on the kidney biopsy.
Take a look at this recentpathology classification of DMII nephropathy. It starts off at classifying it in terms of mesangial expansion and leading to the classic KW lesions. It reminds you of a lupus classification but in this case, its more progressive. This article in JASN published many years ago has been the proposal paper. I am hoping validation studies are underway to confirm this. Does this help us as clinicians? Or is it more for pathologists to have a better handle on how to diagnose DM on kidney biopsy as presentations can be so variable.  Looking at the classification, I think the diagnosis of DM nephropathy will increase. Class I is more of just EM changes of GBM thickening. IIa and IIb are the classic mesangial expansion.  The KW lesion is the cornerstone of Class III and IV is bad advanced diabetic glomerulosclerosis.

Class	Description	Inclusion Criteria
I	Mild or nonspecific LM changes and EM-proven GBM thickening	Biopsy does not meet any of the criteria mentioned below for class II, III, or IV
		GBM > 395 nm in female and >430 nm in male individuals 9 years of age and oldera
IIa	Mild mesangial expansion	Biopsy does not meet criteria for class III or IV
		Mild mesangial expansion in >25% of the observed mesangium
IIb	Severe mesangial expansion	Biopsy does not meet criteria for class III or IV
		Severe mesangial expansion in >25% of the observed mesangium
III	Nodular sclerosis (Kimmelstiel–Wilson lesion)	Biopsy does not meet criteria for class IV
		At least one convincing Kimmelstiel–Wilson lesion
IV	Advanced diabetic glomerulosclerosis	Global glomerular sclerosis in >50% of glomeruli
		Lesions from classes I through III

 Table from JASN paper from above.

What we learned in medical school was one of the secondary causes of membranous GN pattern on injury was diabetes.  Classically, in practice I have rarely seen that. We classically see the mesangial changes and KW lesions. The thickening and EBM changes can appear like Membranous GN on biopsy but there are no classic deposits and there is no mention of those changes on the above classification scheme.  Membranous GN that is primary in nature can likely to co-exist with DM nephropathy. Others have mentioned this as well on websites. There is only one association I found of this in the literature and that was related to potential insulin deposits that were seen in some patients with DM that developed membranous GN and that suggestive of the pathogenetic role in the presentation. 

Diabetes rarely presents as a membranous pattern. The above mentioned patterns are the most common presentations of DMII.

Consult Rounds: Diabetic Fibrillosis- an entity that is forgotten?

This condition was first described in 1970 by Sohar et al when they observed small sized fibrils in the expanded mesangium of diabetic patients with nodular glomerulosclerosis.

This is interesting as in the realm of organized deposits, knowledge of this entity is important as we are embarking on biopsies of diabetics to look for alternate cause of proteinuria. The fibrils may appear to look like Fibrillary GN or Amyloidosis ( although slightly smaller).  To date, no clinical correlation has been noted when these fibrils are seen.

On LM, these fibrils are usually silver stain negative. The degree of decreased argyrophilia depends

on the extent of fibril deposition. The fibrils are only identifiable at the ultrastructural level and can measure from 5-20nm in diameter.  The fibrils are negative for Congo red and Thioflavins T and S.  The pathophysiology might be related to glycosylated expanded diabetic mesangium. Why some get it and some don’t is unclear.

 A nice review comparing organized deposits is presented in the pathology journal.

Amyloidosis is usually Congo red, Thioflavin T or S positive and the fibrils are  7- to 12-nm fibrils, randomly arranged.

Fibrillary GN is usually Congo red, Thioflavin T or S negative, IgG, C3 staining and nonbranching, 15- to 30-nm fibrils, randomly arranged;

Diabetic fibrillosis  is usually nodular GN; Congo red, Thioflavin T or S negative and IF shows linear IgG and albumin  on IF and fibrils are 5–25 nm in nodular mesangial areas

Immunotactoid GN is Congo red, Thioflavin T or S negative with variable microtubules stacked like deposits 10–90 nm

          A recent case that is published describes this entity in more detail. 

Image source: kidneypathology.com.ar

TOPIC DISCUSSION: Renal biopsy findings in Diabetics

A recent study looked at patients who had diabetes and had a biopsy at Columbia Univ path registry.
They wanted to see what other findings are seen besides diabetes. Most of these patients had atleast 10 years of diabetes. Prior reports have suggested IgA and Membranous GN as the most common non diabetic findings in these patients.

1. 37% had Diabetic nephropathy
2. 36% had non diabetic renal disease alone
3. 27% had diabetic neph and another disease
4. In the non diabetic renal disease alone:- FSGS , HTN, ATN, IgA neph, membranous GN, Anca disease comprised most of the diagnosis in that order of frequency.
5. ATN was the surprise finding that had not been reported prior reports.

Interesting and useful data. This is probably lower than expected as most that get a biopsy had a clue for an alternate illness in the kidney. The ones that don't get a biopsy also might have dual disease states that often get missed.

http://www.ncbi.nlm.nih.gov/pubmed/23886566

ROADMAP: Did we forget to use this map?

Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease( so we think). Some people might argue its a word that needs to be taken away from the medical dictionary. In 2011, NEJM published the ROADMAP trial.  They wanted to show if the use of ARB would delay the onset of microalbuminuria or albuminuria in patients with Type 2 DM. In a randomized trial, over 4000 patients were either in olmesartan arm or placebo for close to 3 years. The primary outcome was the time to the first onset of microalbuminuria. 

Interesting results:
1. The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; 
2. Microalbuminuria developed in 8.2% of the patients in the olmesartan group  and 9.8% in the placebo group 
3. The serum creatinine level doubled in 1% of the patients in each group. 
4. Greater number had fatal cardiovascular events in the treatment arm — 15 patients (0.7%) as compared with 3 patients in the placebo arm (0.1%) (P=0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes.

This is striking. Causes:- was it hyperkalemia? was it lower blood pressure than we think should be for DMII. This was reviewed by FDA as well. Other renal blogs had mentioned this trial as well.

Glucoretics have arrived: A new class of anti diabetic drugs

The U.S. Food and Drug Administration approved the drug, Invokana, after data showed it was effective in lowering blood sugar in patients with Type 2 diabetes.
Known chemically as canagliflozin, Invokana is a member of a new class of diabetes treatments called sodium-glucose co-transporter-2 (SGLT2) inhibitors that lower blood sugar by blocking reabsorbtion of glucose and increasing its excretion in urine.
To me this sounds like a glucoretic. 

Some of the animal data had shown promise and then these class of drugs came into trials. Preclinical and clinical research has demonstrated that inhibition of SGLT2, the major pathway of renal glucose reabsorption, leads to increased urinary glucose excretion with concomitant reductions in fasting and postprandial plasma glucose levels, HbA1c levels and body mass. In animal studies, the drugs have been correlated with an increase in urinary volume and a reduction in body fat but not water content.They do mention that it is contra indicated in CKD and ESRD patients( well if you don't make urine, this will not be working for sure).

Why is this drug important for nephrologists? Well increased osmotic diuresis can perhaps lead to a pre renal insults, more urinary tract infections( due to the glucorectic effect), perhaps proximal tubular dysfunction or better yet- maybe it gives additional benefit of water loss leading to good blood pressure control. A recent study already looked at the drug's effect on CKD stage 3 patients. It was deemed safe in CKD Stage 3 based on that one study. 

Novel mechanism, lets wait and watch.

Nodular glomerulosclerosis

Differential diagnosis for nodular glomerulosclerosis on kidney biopsy

The differential is vast but a good way to differentiate is via IF staining
If Immuno is positive, either monoclonal or polyclonal:
Think:- Monoclonal IF:- MPGN, or paraprotein related disease such as LCDD or amyloidosis
If polyclonal IF:- Immunotactoid, fibrillary,cryoglobulinemia and other organized deposits seen in fibronectin GN

If Immuno is negative( more common): 
Diabetic Nephropathy
Chronic TMA
Chronic ischemic disease or hypoxia
Smoking associated nodular sclerosis and or related to metabolic syndrome

Check out a recent quiz on eAJKD on this topic.
Check out the concept map on this to simplify.

eAJKD: Sulodexide in Diabetic Nephropathy: Is There a Role for This Novel Agent?

Check out the latest offering from eAJKD:
http://ajkdblog.org/2011/11/22/sulodexide-in-diabetic-nephropathy-is-there-a-role-for-this-novel-agent

Topic Discussion: Diabetic Nephropathy Post Kidney Transplantation

Post Transplant Porteinuria: Differential Diagnosis:
1. Recurrent Glomerular Disease
2. Denovo Glomerular Disease
3. Antibody Mediated Rejection
4. Infection from CMV or Adenovirus
5. Collapsing Glomerulopathy
6. Thrombotic Microangiopathy
7. Diabetic Nephropathy

What is the data and incidence on Diabetic Nephropathy Post transplant? 

80-100% of diabetics who undergo transplant will have histological changes of diabetic nephropathy, which may be seen within 6 years. Diabetic nephropathy is not believed to be a significant cause of allograft failure, but has not been well-studied. 

•One study that looked at a 5 year prospective trial of 48 pts with type-1 DM underwent renal transplant 

•Patients were randomized to intensive or standard insulin therapy (insulin several times per day/continuous vs 1-2 times daily); statistically significant difference in A1C maintained . The five year  post-transplant biopsy showed standard group had 2x increased volume of mesangial matrix (p=0.024) and 3x increase in arteriolar hyalinosis, wider basement membrane(p < 0.10). 

Understudied disease but by far the MOST common cause of proteinuria years following a kidney transplantation.

Post by Prasanth Krish, MD
Renal Fellow, Hofstra NSLIJ

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/15265161

http://www.ncbi.nlm.nih.gov/pubmed/8830828

http://www.ncbi.nlm.nih.gov/pubmed/3548353

http://www.ncbi.nlm.nih.gov/pubmed/8057515