Bardoxolone - The Final Chapter - Part 2

One of the issues surrounding the study of bardoxolone in animal models was that, because of the way that it is metabolized in rats and mice, it is highly toxic when given for long periods. This specific toxicity is not present in humans. As a result, it was not possible to study the drug directly. An alternative was to study analogues of the drug. A group from Italy have just published the results of a study of an analogue of bardoxolone, RTA 405, in rats with type 2 diabetes. This study was accepted for publication before the termination of the beacon trial but raised some important concerns which are even more salient now.

RTA 405 caused significant weight loss and elevation of transaminases in treated rats. Also, proteinuria increased threefold. When this rat model is treated with ACEi, there is normally a decrease in proteinuria and renal damage. When the rats were treated with RTA 405 and an ACEi simultaneously, there was some reduction in proteinuria but not to baseline. The proteinuria was accompanied by evidence of severe glomerular and tubular damage.

It is possible that these results are due to a metabolite of RTA 405 which may not be present in humans and as a result, the findings are not necessarily generalizable to humans. However, these adverse effects are similar to those initially reported in the NEJM. The mechanism for the increased renal injury is uncertain at this time.

Previous posts on this topic are here, here, here, and here

eJournal Club - Albuminuria and AKI

This month’s eJournal club concerns biomarkers of AKI. There has been considerable interest in developing novel biomarkers of AKI and CKD and a lot of effort has been focused on novel biomarkers such as NGAL, KIM-1 and IL-18. The TRIBE-AKI consortium has published a number of well-designedstudies investigating novel and traditional biomarkers. The reason that these biomarkers are desired is because creatinine elevations tend to occur relatively late in the course of AKI and therefore, the sense is that this is too late to initiate therapies which may prevent progression of AKI. However, the results of these biomarker studies have been relatively disappointing and they have not yet entered regular clinical practice.

This month in CJASN, a study was published looking at the performance of post-operative albuminuria as a biomarker of AKI in patients following cardiac surgery. The highest quintile of albuminuria was associated with a RR of 2.97 for AKI relative to the lowest quintile. While this appears good and the AUC for a model including albuminuria to predict AKI was 0.81, the majority of patients with albuminuria did not develop AKI and the model missed a significant number of patients with AKI. Still, when you combine this with other studies showing that the urinalysis is an excellent predictor of outcome in patients with AKI, older biomarkers are not looking so bad after all. Perhaps we will be able to come up with a combination of biomarkers which will allow us to better predict those patients at greater risk of AKI. To me, it seems that the bigger issue is low sensitivity rather than low specificity. I would rather have a model which will allow me to rapidly rule out those who will not develop AKI than one that will misclassify patients into a low risk group.

It was interesting in this study that ACR was not a good predictor of AKI – the absolute level of albumin performed better. This is at odds with the majority of studies which suggest that albumin should be corrected for creatinine level. This is possibly due to the large variation in creatinine generation in patients in the ICU – although relatively constant under normal circumstances, the amount of creatinine produced daily changes rapidly in sick patients – as was evidenced by a recent study of creatinine excretion in patients on CRRT.

Bardoxolone - Part 3

Last year, we had a post about Bardoxolone for the treatment of diabetic nephropathy. After one year of treatment, eGFR increased significantly in patients treated with Bardoxolone relative to controls. At the time, significant concerns were raised about the fact that albuminuria also increased in patients receiving the drug and it was uncertain both what the mechanism of this was and whether there would be any deleterious consequences. 

This week, an article was published in JASN which goes some way towards explaining the reason for the proteinuria. Under normal circumstances, a significant quantity of albumin is filtered in the glomerulus. Almost all of this albumin is reabsorbed in the proximal tubule by the cubilin-megalin complex. Defects in cubilin and megalin have been associated with albuminuria in animals and humans. It turns out that Bardoxolone downregulates the expression of megalin in monkeys in the proximal tubule. Thus, the increase in albuminuria may be due to decreased effectiveness of the retrieval process. At one year, there were no significant differences in renal histology between the treated monkeys and controls. 

This is a fascinating finding. There has been a lot of work done in the last few years regarding the effect of albuminuria itself on renal fibrosis. Even in the absence of any vascular changes, overload albuminuria is associated with increased fibrosis in animal models. So, why is there no damage seen in these monkeys? One of the postulated mechanisms of albuminuria-induced fibrosis is that megalin itself acts as a transmembrane receptor and stimulates EGF production in the presence of excess tubular albumin. This ultimately leads to increased interstitial fibrosis. The loss of megalin in treated monkeys means that this pathway might be downregulated. It should be said that these were healthy monkeys and the effect in humans with more albuminuria at baseline could be different. That said, this study goes some way towards alleviating some of the concerns that were raised last year.

Still mysterious: the elusive circulating factor for FSGS

Important new findings were recently published in relation to proteinuria and FSGS, which are definitely of interest to our community.

First, the punch line:

There is new evidence for a “circulating factor” in recurrent FSGS in a fascinating case of a re-transplanted kidney (here)

BUT

There is growing evidence that suPAR is a non-specific marker of kidney disease and therefore not likely to be the “circulating factor.”(here)

In fact, it appears that it is non-specifically found in CKD, and correlates with a declining GFR.

Now for some details:

The re-transplanted kidney

A letter to the NEJM editor (here) describes an amazing case of resolution of recurrent FSGS after re-transplantation. 

A 27 year old patient with primary FSGS receiving a kidney from his healthy 24 year old sister developed proteinuria in the nephrotic range (up to 25 g/day!) within 2 days of transplantation, and had no improvement after plasmapheresis and standard immunosuppressive treatment. A renal biopsy confirmed foot process effacement, the first hallmark of recurrent podocyte damage heralding recurrent FSGS. Incredibly, with all appropriate consents and institutional approval, the transplant team removed the allograft from Patient 1 and re-transplanted it into another patient who had ESRD due to diabetes. Within 3-4 days, the proteinuria resolved and a repeat biopsy showed resolution of foot process effacement and re-establishment of a normal podocyte architecture. Eight months later, Patient 2 is reported to be doing very well, with good allograft function and no proteinuria.

This case demonstrates in a remarkable way that recurrent FSGS results from an elusive “factor” rapidly produced by the recipient (with primary FSGS), and that the allograft itself can remain fully functional if removed from the influence of this “factor” and placed in another patient.

suPAR is not suPER specific

What may have seemed to be exciting news in 2011, namely the notion that soluble uPAR may be predictive of recurrent FSGS (here), appears to be unfortunately evolving into yet another unsuccessful attempt to identify the ever elusive circulating factor.

Recent work published in Kidney International by Maas et al. (here) confirms that suPAR is not able to distinguish between idiopathic FSGS, secondary FSGS or minimal change disease. 

This is actually not surprising, because a closer look at the clinical data in Wei et al. (here) reveals that the admittedly arbitrary cut-off for separating primary FSGS from all other glomerular disease (3000 pg/ml) did not hold up when tested among their patient cohorts with idiopathic, recurrent versus non-recurrent FSGS (all had suPAR> 3000 pg/ml, thus suPAR could not predict the recurrent from the non-recurrent cases). 

The second figure in the Maas et al. paper may help explain this conundrum: they show a negative correlation between suPAR and eGFR, meaning that as GFR drops, suPAR levels rise, which essentially means that suPAR is simply a marker of CKD.

Future work will no doubt continue to address these issues, but the apparent lack of specificity of suPAR for FSGS casts serious doubt on its proposed role as the circulating factor.

So, the search is still on!!!

Under Pressure

As a medical student I was taught the CKD hypertension gospel straight from the good book of JNC VII: Thou shalt lower the blood pressure to less than 130/80! This was many years after David Bowe and Freddie Mercury but I got the song stuck in my head when I started thinking about the post so I had to put it up there.

I lived happily with this for many years until one day someone questioned me. Why should you lower the blood pressure to less than 130/80 in someone with chronic kidney disease? Well 'cause the JNC VII says so! Check it out...


Right there in red, blue and black. And supported by two references no less! One of them is the American Diabetic Association going on about diabetes (another story) but reference 21 is KDOQI on CKD... So the rabbit hole gets deeper.

Over at KDOQI we get the following...


They say "controlled trials in essential hypertension conclusively show a beneficial effect of lowering blood pressure to <140/90 mm Hg. Controlled trials in high-risk individuals with diabetes or heart failure suggest beneficial effects of reduction of blood pressure to even lower values. Based on these studies, and on observational studies, a number of guidelines for patients with either diabetes mellitus or congestive heart failure recommend a goal blood pressure of <130/80 mm Hg. There are few studies regarding blood pressure goals for CVD risk reduction in patients with CKD. Thus, the Work Group elected to extrapolate the recommendations for high-risk patients to patients with CKD."

Uhh so, we have no evidence so we took some evidence from other diseases and said do the same thing. It not quite that bad. There is some evidence for less than 130/80 but it has caveats.

The MDRD study randomized patients to aggressive vs standard blood pressure control with achieved average values of 126/77 and 133/80 respectively. At the end of the study there was no overall difference between the two groups in terms of kidney function but in post-hoc analysis the aggressive BP arm had statistically slower rates of renal function decline in patients with over 1g per day of proteinuria mainly driven by patients with over 3g of proteinuria per day. Unfortunately, the aggressive control group were more likely to have received ACE inhibitors than the standard control group so the post-hoc data is a bit muddled.

In the recently published long term followup of the AASK trial, African Americans with hypertensive kidney disease who were initially randomized to either intensive or standard BP control were subsequently followed in a cohort phase in which the BP target was the same in both groups. Followup extended out to 12 years from the initial randomization. The achieved BPs during the trial were 130/78 mm Hg vs 141/86 mm in the intensive and standard groups respectively. In the cohort phase BPs were much closer as expected (131/78 and 134/78 in the intensive and standard groups respectively).

The story is similar to MDRD, among all patients there was no difference in the primary composite outcome of ESRD, doubling of serum creatinine or death throughout the trial and cohort phase. However, in the subgroup with baseline proteinuria of greater than 220 mg per day a significant difference between BP target groups appeared favoring more intensive control.


So no clean randomized prospective data to support the JNC VII target of less than 130/80 in CKD patients. There is a hint from the above subgroup analyses that CKD patients with proteinuria might benefit from having blood pressures controlled to below 130/80. The proteinuria cutpoint at which this might occur is unclear.

It will be interesting to see how JNC VIII, expected sometime later this year, handles the above. Additional information will hopefully come from the randomized prospective SPRINT trial which is looking at systolic BP goals of 140 vs 120 in a large cohort with a reasonable proportion of CKD patients.