Plasma Exchange for Severe ANCA-Associated Vasculitis (AAV)?

There has been lots of new data in the AAV literature of late. We have new nomenclature, including the dropping of Freidrich Wegeners name for the more generic but descriptive granulomatosis plus angiitis (GPA), by the Chapel Hill consensus conference. A large genome wide association study by the European Vasculitis Genetics Consortium has reported genetic variants associated with AAV and show that polymorphism segregate with ANCA specificity (Anti-MPO and Anti-PR3). A recent follow-up to the RAVE study demonstrates non-inferiority of rituximab as compared to oral cyclophosphamide for severe AAV. Moreover, among patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression, at least for the first year.

Removing pathogenic antibodies via plasma exchange (PE) is an attractive, if crude, treatment option for severe AAV and is generally recommended for severe alveolar hemorrhage (although without much evidence). In patients without severe lung involvement, it has gained a role in attempting to prevent ESRD in patients with severe renal disease at presentation, due largely to the MEPEX trial. MEPEX was published in 2007 and included patients with AAV who required dialysis at presentation or had a serum creatinine >500 µmol/L (5.8 mg/dL). This study included 137 patients who were randomized to 7 PE treatments or IV methlyprednsiolone pulse therapy. Both groups received oral steroids and cyclophosphamide. PE was associated with a risk reduction of ESRD of 24% at 1 year. Patient survival and severe adverse event rates were similar in the 2 groups. A follow up to MEPEX has been published in Kidney International this month where the original patients were followed for a median of 3.95 years. During this follow-up, over a half of patient died and almost two-thirds had either died or developed ESRD (the composite primary outcome), with no significant difference between the groups. Also, there was no significant differences in relapse rate.

It must be noted that the original MEPEX trial was designed to examine rate of ESRD alone and demonstrated a benefit with PE at 1 year. The current study looks at a composite of ESRD & death at 4 years. If the early effect on ESRD if real, it would be intuitive that later mortality would be improved which it seems is not. Overall this study questions the benefit of PE in severe AAV and certainly dampens our enthusiasm for its use in this sick patient cohort. A criticism of MEPEX is that IV methlyprednisolone is considered a standard of care in initial treatment of severe AAV and not an alternative to PE. In the real world, patients would receive IV methylprednisolone plus PE. It is also very possible that a beneficial effect of PE exists in cases of AAV earlier in their natural history before significant scarring has occurred, as suggested by a meta-analysis. At this point, PE can certainly be considered as part of the armamentarium of AAV treatment but its exact indication is unclear. The ongoing PEXIVAS trial is planned to enroll 500 patients and will hopefully clarify the role of PE, if any, in severe AAV.

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!!!

Antibody-Mediated Rejection: Choose your weapons

Acute humoral or antibody-mediated rejection (AMR) is attributed to the presence of alloantibodies against the graft, which could be either antibodies against human leukocyte antigens (HLAs) Class I and/or II , non-HLA antigens or endothelial antigens. Diagnosis of AMR is made through tissue biopsy and presence of alloantibodies. Early treatment is of paramount for the preservation of graft function. Treatment strategies include removal of alloantibodies, decreasing or stopping production of alloantibodies, or attenuating the immune systems response to alloantibodies. 

Plasmapheresis/Plasma Exchange 

Removal of alloantibodies is done through the use of plasmapheresis/plasma exchange or immunoadsorption. Plasmapheresis, or removal and replacement of one plasma volume, is effective at removing approximately 60% of the intravascular IgG which accounts for about 75% of the intravascular immune response. Extravascular IgG equilibrates in about 48 hours thus reducing total body IgG concentrations and reducing the effective immune response. Immunoadsorption works similarly to plasmapheresis except that plasma immune complexes and IgG are removed via protein A bound silica matrices. In the latter, the remaining plasma components are returned to the patient without the need for plasma exchange. FFP is needed even on the first run of plasmapheresis if recent biopsy was performed (prevention of bleeding). The cost of 5 treatments is about $4,600. 

Intravenous Immune Globulin 

Infusion of intravenous immunoglobulins (IVIG) has been studied at doses of 10 grams to 2 gm/kg as monotherapy or in conjunction with plasmapheresis or B-cell depleting agents. The mechanism of action is not entirely known but it is thought that neutralization of alloantibodies occurs when bound by the anti-idiotypic antibodies in IVIG as well as diminished plasma cell production by increasing total body concentrations of immunoglobulins and direct T-cell and complement cascade effects. Cost for IVIG is $77.06/gm resulting in $770.60 or $10,788.40 (dose intensity), based on a 70kg patient for each dose. 

Decreasing or stopping the production of alloantibodies requires therapies directed against mature plasma cells, memory B-cells or plasmablasts. Targeting memory B-cells or plasmablasts has a delayed onset of action as this therapy prevents new plasma cells from being formed but does not affect currently active ones. 

Rituximab 

A chimeric anti-CD20 monoclonal antibody, is dosed 375 mg/m2 or 1000 mg IV and given for one to two doses. The CD20 receptor is found on the surface of B-lymphocytes, including memory B-cells and immature plasmablasts, but not plasma cells. Rituximab has cytotoxic activity directly reducing B-lymphocyte and antibody levels. Cost for therapy ranges from $4,923.78 for dosing based on normal body surface area to $7,589.64 for a 1000mg dose. 

Bortezomib 

A proteasome inhibitor, is dosed 1.3 mg/m2 IV and given for four doses on days 1, 4, 8, and 11. Proteasome inhibition prevents protein biosynthesis resulting in apoptosis of the plasma cell and cessation of alloantibody production. Cost per dose based on a normal body surface area is $1,134.27. 

Eculizumab 

A humanized monoclonal antibody directed against C5, is dosed 600mg to 1200mg IV and administered weekly depending on alloantibody concentrations. Prevention of AMR is mediated by inhibition of membrane attack complex formation and halting activation of the complement cascade. Eculizumab is supplied as a 300mg vial for $6,638.40 or $13,276.80 to $26,553.60 per dose. 

Increasing the dose of maintenance immunosuppressive agents, including calcineurin inhibitors, antimetabolites, and steroids are also used to attenuate the immune system and help alleviate AMR. With all of the available treatment options, a multimodal approach is usually recommended to maximize chances of preventing graft injury. However, as you might see from the numbers above, careful clinical decision must be based on both efficacy and cost in order to responsibly avoid collapsing our already broken health care system. Instead of each center using its on protocol, our society should get together and perform a randomized trial with those interventions. Though I doubt this will happen any time soon, in particular with all the NIH budget cuts...

David Reardon, PharmD, PGY2 Critical Care Resident

Steve Gabardi, PharmD

Leonardo V Riella MD PhD (editing role)