Diabetes: To Biopsy or not to Biopsy - Part 2

In my experience the appetite to biopsy patients with clinical renal disease varies widely between clinician, institution and country. This is most apparent when it comes to the diabetic patient with renal disease. In my opinion there is a fear among nephrologists of biopsying patients with potential diabetic nephropathy (DN). Of course there are clinical features that increase the likelihood that a diabetic with renal disease has DN. Retinopathy in a type 1 diabetic, longstanding DM and progressive proteinuria over years preceding an elevated creatinine. However, the role of microalbuminuria and proteinuria in predicting CKD progression and the traditional course of rising albuminuria in DM1 has been challenged. In DM type 2 the picture is less clear and these patients frequently have many comorbidities. Gearoid posted on this subject about a year ago now. In CJASN (October) Sharma et al from Columbia University reviewed the characteristics and renal diagnoses in 620 diabetics who had a renal biopsy. Over 90% had type 2 diabetes. In Columbia in 2011 approximately ¼ of all biopsies were on patients with diabetes. The results of this retrospecive review were that 37% of patients had DN alone, 36% had non-diabetic renal disease (NDRD) alone, and 27% had DN plus NDRD.

In NDRD alone: FSGS (22%), hypertensive nephrosclerosis (18%), acute tubular necrosis (ATN) (17%), IgA nephropathy (11%), membranous GN (8%), and pauci-immune GN (7%) comprised 80% of diagnoses.

In DN plus NDRD: ATN (43%), hypertensive nephrosclerosis (19%), FSGS (13%), and IgA nephropathy (7%).

In multivariate analysis longer duration of DM was associated with a greater likelihood of DN and less likelihood of NDRD.

The table illustrates the features of patients at the time of biopsy. Older age, having DM2 vs DM1, short duration of DM and less proteinuria are more likely in those with NDRD alone vs DN alone in this cohort. 

I think this study highlights the importance of considering biopsy in diabetics (especially type 2). I would be interested to hear about the experience of others with respect to biopsy in diabetics.

Posted by Andrew Malone

Characteristics	DN Alone	DN Plus NDRD	NDRD Alone
Participants (n)	227	164	220
Age (yr)	59 (49–65)	63 (55–72)	63 (54–70)
Male sex	129 (56.8)	100 (61.0)	142 (64.6)
Race
Unknown	108 (47.6)	57 (34.8)	104 (47.3)
White	62 (27.3)	63 (38.4)	70 (31.8)
African American	39 (17.2)	33 (20.1)	29 (13.2)
Hispanic	12 (5.3)	7 (4.3)	8 (3.6)
Asian	4 (1.8)	4 (2.4)	7 (3.2)
Other	2 (0.9)	0 (0.0)	2 (0.9)
DM type 1	9 (4.0)	5 (3.1)	2 (0.9)
Duration of DM (yr)	13 (8–17)	10 (7–18)	5 (3–10)
Serum creatinine (mg/dl)	2.3 (1.6–3.8)	3.1 (1.7–5.2)	2.3 (1.5–4.4)
eGFR (ml/min per 1.73 m2)	31.3 (17.5–55.2)	21.4 (12.5–46.6)	32.5 (14.3–60.0)
Proteinuria (g/d)	5.0 (2.8–8.8)	5.0 (2.0–8.0)	2.9 (1.4–7.1)

Diabetes and CKD - Pitfalls: Cystatin C

Cystatin C has been proposed as an alternative marker of kidney function and studies have shown that CyC is a better predictor of mortality that serum creatinine. Although, when first introduced, it was thought that CyC was not influenced by factors apart from renal function, this assumption has been questioned in the recent past.

CyC is a 13 kDa cysteine protease inhibitor that is produced by all nucleated cells. It is freely filtered at the glomerulus and then catabolized in the proximal tubule such that very little appears in the urine. CyC levels are affected by renal function but also independently influenced by age, gender, BMI, fat mass, triglycerides and the presence of diabetes. Interestingly, these are all components of the metabolic syndrome.

In 2011, a paper was published in Diabetologia that found that elevated levels of CyC were associated with an increased incidence of type II diabetes. The thought was that CyC was potentially involved in the pathogenesis of diabetes. In July, a paper was published in NDT that shed a bit more light on this issue. The authors reported the results of a 3-year study of French adults in whom the incidence of diabetes was low. In this study, in common with previous research, CyC predicted incident diabetes. However, when stratified by BMI, CyC predicted incident diabetes only in participants with a BMI >25 at baseline.

So what is the explanation for this? CyC secretion has been shown to be 2-3 times higher in obese patients than in non-obese patients. CyC is also highly expressed in subcutaneous adipose tissue. Data from the Framingham Heart Study has shown that adipose tissue was not associated with CKD using creatinine-based estimating equations while it was associated with CKD using a CyC-based equation. CyC may play a role in preventing inflammation associated with increased adiposity explaining the increased secretion in obese patients.

The implications of this are that, although CyC may predict diabetes, it is unlikely that it adds any more to prediction algorithms considering that it is not independent of BMI and the metabolic syndrome - both of which are well known to be associated with diabetes. The second implication is that the fact that CyC is better at predicting mortality than creatinine (at the same level of eGFR) is related to non-renal factors - again, adiposity and the metabolic syndrome. It similarly suggests that in obese patients, estimating equations that utilize CyC may not be as accurate as previously suggested. The search for a better biomarker of GFR continues...

Heavy Metal

The excellent drug development blog "In the pipeline" highlighted a fascinating phase 2 trial that is ongoing at the moment. Pentoxifylline is a methylxanthine phsophodiesterase inhibitor that has been used to treat peripheral vascular disease. It is also known to have anti-inflammatory properties and a recent Cochrane meta-analysis suggested that there may be a benefit in patients with diabetic nephropathy and albuminuria. The trial mentioned above is of an analog of one of the active metabolites of pentoxifylline called CTP-499. The clever thing about this molecule is that it is deuterated.

Deuterium is an isotope of hydrogen. Hydrogen typically has a single proton and no neutrons. Deuterium is a hydrogen atom with an added neutron. The thing that makes this interesting to drug companies is that it forms stronger bonds with other atoms than traditional hydrogen. As a result, liver enzymes take longer to break down a drug that has deuterium substituted for hydrogen and thus the half-life of a medication can theoretically be extended. There has been a rush recently to patent various drugs that have been "deuterated" although it is uncertain at this time whether or not this is going to be a successful strategy. There really are few safety concerns - the deuterated hydrogen would eventually form D2O or heavy water in the body prior to being excreted. Although too much heavy water would be deleterious, you would have to drink liters before you would see any adverse effects and the effect of these medications is likely to be minimal.

Bardoxolone - The final chapter?

Sometimes when something appears too good to be true, it is too good to be true. Last year, a paper was published in the NEJM reporting a preliminary study of bardoxolone for the treatment of diabetic nephropathy. At the time, this seemed like it might be promising but there were a number of issues with the study including the use of eGFR as an endpoint and the fact that the use of the drug was associated with a significant rise in albuminuria, both of which we raised here in a blog post. More recently, we posted again on this drug. An experiment in monkeys revealed that bardoxolone downregulated the expression of megalin in the proximal tubule and that this may have been responsible for the increase in albuminuria.

All this time, a phase 3 study was ongoing to determine what the true effect of the drug was in a larger group of patients. Unfortunately, it was announced last week that the trial had been stopped. According to an article in marketwatch, there were "excess serious adverse events and mortality in the bardoxolone methyl arm" according to the monitoring committee. We don't know yet what exactly happened and the company is not releasing any more data beyond this simple statement. I am sure more information will come out in the future.

This is extremely disappointing. For all that it seemed too good to be true, there are so few things that we have in our toolbox to delay the progression of diabetic kidney disease that this was potentially a blockbuster treatment for this condition. There may be aspects of this drug that remain useful in some specific circumstances and it may also aid in future drug development. We will not know the answers to these questions until the final study results are published.