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

Diabetic Nephropathy, or not?

A man in his 30s with a history of type 1 DM and chronic hypokalemia was referred to the renal clinic for investigation of CKD. His creatinine was 1.8g mg/dl.  His DM was well controlled without any evidence of retinopathy.  Urinalysis did not show any proteinuria or hematuria.  His renal biopsy showed focal tubular atrophy, dystrophic calcification in the scattered tubules, and did not have any signs of diabetic nephropathy.  His renal biopsy findings were therefore attributed to chronic hypokalemia.

Hypokalemia can cause kidney damage if it persists for longer than one month.   Chronic hypokalemia can cause non-specific vacuolar lesions in the epithelial vessels in the proximal tubules.  Typical renal biopsy will show interstitial nephritis, fibrosis, tubular atrophy and cyst formation.  The pathogenesis of hypokalemic nephropathy is not clear.  The hypotheses are:  1) complement activation and tubular cell damage by hypokalemia induced renal ammonium production 2) stimulation of cell growth and proliferation by intracellular acidosis 3) increased production of growth factors (VEGF, IGF-1) and cytokines by hypokalemia through an uncertain mechanism.

After further work-up, our patient was diagnosed with Giltelman syndrome.  He was started on potassium replacement and his Cr has remained stable since then.  

Posted by Jie Cui

Peripheral Vascular Disease and CKD

Seminars in Dialysis this month have published an excellent review of the diagnosis and treatment of peripheral vascular disease in patients with CKD. This is something that we deal with on a regular basis in the clinic and I was surprised to see that we had not dealt with this topic before on RFN. Some salient points from the article:

PVD is common in the US population and the prevalence increases with age - up to about 15% in patients over the age of 70. The prevalence of PVD in patients with CKD is far higher, one study from Italy found that 32% of patients attending a CKD clinic who were asymptomatic, had an ABI of less than 0.9 which is the traditional threshold for diagnosing PVD. Another study using NHANES data found that an eGFR of less than 60 was associated with an OR of 3.0 for PVD after full multivariable adjustment. PVD is independently associated with cardiovascular mortality and the cardiovascular risk increases as the ABI decreases. This suggests that the presence or absence of PVD could help further risk-stratify patients with moderate CKD.

Interestingly, the pathophysiology of PVD in patients with CKD (particularly those with ESRD) is different from the general population. In these patients, the primary culprit is medial calcification rather than atherosclerotic plaque formation and as a result, they often present with diffuse distal disease which is not necessarily amenable to surgical/radiological intervention. The current KDOQI guidelines recommend screening for PVD in all patients on initiation of dialysis although they do state that this guideline is not backed by much evidence and that "further research is needed". Results for primary revascularization in dialysis patients tend to be poor and there is a high rate of lower limb amputation. One issue is that dialysis patients (and those with advanced CKD) tend to have significant hardening of the arteries due to the degree of calcification and this can falsely elevate the ABI. For this reason, the authors of the review do not recommend screening of all patients with CKD and instead suggest a focused examination at each visit with a detailed history and aggressive treatment of cardiovascular risk factors. For patients who are symptomatic, an ABI followed by angiography (if refractory to medical therapy or critical ischemia) is the approach to take.

The authors have a number of nice flowcharts suggesting algorithms for the diagnosis and management of PVD in patients with CKD and I recommend giving the article a look.       

CKD Guidelines

AJKD this month has an extended editorial section on the KDOQI guidelines for CKD. It is now 10 years since these guidelines were introduced and their impact on nephrology has been significant, not least due to the fact that many more patients are now recognized as having early CKD that may have been missed in the past. These patients with moderately reduced GFRs, while unlikely to progress to ESRD, still have a significantly increased risk of cardiovascular morbidity and mortality. 

The articles comprise a series of commentaries written by members of the editorial board of AJKD and examine the impact of these guidelines on the NKF itself, research, primary care, clinical laboratories (which now routinely report eGFRs) and the practice of nephrology around the world.

Hawaii and Population Management

How familiar are the following scenarios to you?

You're in clinic and have just seen a 69 year old man with a longstanding history of hypertension.  He has been referred by his internist to nephrology for an eGFR of 51 ml/min/m2.  He has a bland urinalysis, an unremarkable renal ultrasound and a urine microalbumin to creatinine ratio of 20 mg/g. The patient and his internist have his blood pressure under good control and have addressed other modifiable cardiovascular risk factors.

You've seen this case a million times, right?

How about this one...

You are called to the Emergency Department to see a 51 year old morbidly obese female with a longstanding history of type 2 diabetes and hypertension who has just presented after several weeks of fatigue and pruritis now accompanied by nausea and vomiting.  Her labs show anemia, hyperphosphatemia, hypocalcemia, acidosis, hyperkalemia and marked uremia.  A subsequent renal ultrasound shows small echogenic kidneys.  During the hospitalization she begins maintenance dialysis with a tunneled catheter with a plan for her to continue in-center dialysis 3 times a week on discharge. 

The patient had never seen a nephrologist prior to her hospitalization.

Sadly, this case is familiar too, right?

The two cases above highlight the over and underutilization of nephrology resources in our current care system.  Individuals like the 69 year old man in the first scenario gain little value from a visit to the nephrologist.  The risk of him every progressing to need for renal replacement is incredibly low and the services which he needs (CV risk factor control) are competently provided by his internist.

In contrast, the woman in the second scenario is representative of some 40% of patients who start dialysis today who have never seen a nephrologist prior to beginning renal replacement.   Only 25% have seen a nephrologist for at least year prior to ESRD.  Patients like the woman in the scenario would clearly benefit from disease progression delay strategies, modality education (home, center, transplant) along with appropriate preemptive dialysis access placement (AVF, AVG or PD catheter - depending on modality choice) - all services that nephrology provides.

In light of the above it's encouraging to see the ongoing efforts of organizations like Kaiser Permanente (KP) Hawaii who recently published more results from their experience with proactive population management.

In their system, an electronic tool sweeps the electronic medical records of the entire KP Hawaii population monthly for two basic parameters: eGFR and proteinuria.  Patients are divided into high and low risk groups for progression to need for renal replacement.  A nephrologist reviews the list regularly and proactively reaches out to primary care physicians to bring unrefereed high risk patients into nephrology care.  The patients at lower risk remain or return to primary care with remote physician-to-physician mentoring from the nephrologist.

In an initial report, their system was associated with an increase in the fraction of patients starting dialysis with a mature AVF (18% vs 36%), the fraction beginning dialysis as outpatients (35% vs 56%) and a higher proportion of new referrals consisting of high risk patients (16% vs 35%) and a lower proportion of patients at low risk (50% vs 30%).  There was a nice shift towards dedicating more nephrology new referral effort towards individuals who theoretically derive the most benefit from it with a downstream improvement in dialysis specific outcomes.  As this was a pre- to post- intervention comparison there are the usual caveats about whether there was a change in the population or some other concurrent change that contributed to the shifts in outcome.

In the followup report a smaller portion of patients showed progressive CKD when they were matched by propensity score to a historic cohort.  Although this may have been in part due to improvements in management of blood pressure and proteinuria in the primary care setting through remote nephrology mentoring I have to imagine that the internal blood pressure goal and education initiatives mentioned in the discussion played a substantial role.

Despite the weaknesses of the above studies the idea of proactive risk segmentation of a CKD population with appropriate application of nephrology resources is a highly appealing one.  We have only just scratched the surface of how to incorporate information technology into medical practice and efforts like the above to leverage the data contained within the electronic medical record are a way forward.

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!!!