The evidence behind the use of plasmapheresis in glomerular diseases

Therapeutic plasma exchange (PLEX) is a type of therapy where a patient’s plasma volume is removed over a period of a few hours, through a process of centrifugation of blood with subsequent separation of its constituents, and replaced by different types of colloid fluids, most commonly Albumin or Fresh Frozen Plasma (FFP). Its most frequent use in nephrology is for certain glomerulopathies such as ANCA-associated vasculitis, anti-GBM disease, recurrence of idiopathic FSGS post-transplant and atypical HUS. The data with regards to PLEX use for these indications is mostly historical and based on mechanistic concepts which led to multiple observational studies and reports claiming efficacy. There are very few randomized trials directly comparing PLEX to other therapies and a review of the data (see table summary of KDIGO recommendations) has really brought me a new perspective on what justifies our use of PLEX for renal disease.

Table: KDIGO recommendations on PLEX use for glomerular disease

	KDIGO recommendation	Grade
Anti-GBM disease	We recommend initiating immunosuppression with cyclophosphamide and corticosteroids plus plasmapheresis in all patients with anti-GBM GN except those who are dialysis-dependent at presentation and have 100% crescents in an adequate biopsy sample, and do not have pulmonary hemorrhage	1B
	Start treatment for anti-GBM GN without delay once the diagnosis is confirmed. If the diagnosis is highly suspected, it would be appropriate to begin high-dose corticosteroids and plasmapheresis while waiting for confirmation	Not graded
ANCA-associated vasculitis	We recommend the addition of plasmapheresis for patients requiring dialysis or with rapidly increasing SCr	1C
	We suggest the addition of plasmapheresis for patients with diffuse pulmonary hemorrhage	2C
	We suggest the addition of plasmapheresis for patients with overlap syndrome of ANCA vasculitis and anti-GBM GN, according to proposed criteria and regimen for anti-GBM GN	2D
Post-transplant FSGS	We suggest plasma exchange if a biopsy shows minimal change disease or FSGS in those with primary FSGS as their primary kidney disease	2D
Atypical HUS	Not mentioned in KDIGO guidelines

Adapted from: Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9:S1; and Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney international. 2010 Feb 2;77(4):299-311.

Anti-GBM disease

Anti-GBM disease has always been regarded as a sine qua non indication for PLEX.  I still remember my first teachings on anti-GBM disease in medical school which were were it causes lung hemorrhage, it causes acute kidney injury and it is treated with plasmapheresis. When reviewing the literature, I was surprised to find only a single randomized trial on the use of PLEX in anti-GBM disease. This a study published in 1985 in Medicine by Johnson et al where they randomized 17 (yes, only 17!) patients with biopsy and serology proven anti-GBM disease to either Prednisone + PO Cyclophosphamide (N=9) vs PLEX + Prednisone + PO Cyclophosphamide (N=8). Patients at baseline were not equally matched as the patients in the conventional group had higher serum creatinine (SCr) at start of therapy and had more severe disease on biopsy. Indeed, 5/8 biopsies available had >70% gloms with crescents in the conventional group vs only 1/7 in the PLEX group had > 50% gloms with crescents. They did find that more patients were dialysis dependent at the end of the study in the conventional group (6/9) vs the PLEX group (2/8). Four patients in the PLEX group had improvement in their renal function vs only 1 in the conventional group. These patients who had improvement were the ones with lower SCr at presentation. Eight patients had pulmonary hemorrhage (4 in each group) and all these episodes were treated with IV Methylprednisone pulse and responded promptly. There were only 3 deaths in all, 1 in conventional and 2 in PLEX group. Anti-GBM titers became undetectable much more quickly with PLEX, after about 2 months. Overall, it is somewhat surprising that what we consider such a strong indication for PLEX is supported by only 1 randomized trial showing improved renal survival with PLEX, where the groups were unevenly matched. What is also important to consider with anti-GBM disease is the possible futility of treatment in patients with most severe disease. A review of anti-GBM disease in the UK from 1980-1984 by Savage et al looked at outcomes for 108 patients. There were 69 patients who were dialysis dependant on presentation. At 8 weeks, none were off dialysis (51 on dialysis and 18 dead). Out of 12 who presented with a SCr>600umol/L, only 1 had improvement in renal function (other 11 either on dialysis or dead). Another British study published in 2001 in the Annals of Medicine by Levy et al retrospectively looked at all anti-GBM disease treated at the Hammersmith hospital in since 1975. They had 71 patients, 39 of which were dialysis-dependant on presentation. Only 2 were off dialysis at 1 year follow-up. When looking at outcomes based on biopsies, they found that 23% of patients with >50% crescents survived off dialysis and that 3 patients survived off dialysis despite >70% crescents. However, no patients with 100% crescents recovered renal function. Together, these results certainly seem to suggest that patients with severe anti-GBM disease presenting dialysis dependent have very little chance of recovery and may not benefit at all from immunosuppressive therapy and PLEX. While a trial of treatment may still be indicated, I believe a rapid re-assessment of the patient’s condition and need for continued immunosuppressive therapy is indicated given the high infectious risks with treatment. Patients with 100% crescents on an adequate biopsy are very unlikely to get any benefit and should probably just be managed conservatively.

ANCA-associated vasculitisAnother frequent indication for PLEX in glomerular disease is ANCA-associated vasculitis and thankfully there is a bit more data to guide us here. The best data comes from the MEPEX trial by Jayne et al published in JASN in 2007 where 137 patients with biopsy/serology proven ANCA vasculitis and SCr > 500umol/L were randomized to either PLEX (7 exchanges in 14 days) or IV methylprednisolone (1g IV daily x 3), both in combination with oral Cyclophosphamide and Prednisone. Patients with severe lung hemorrhage requiring mechanical ventilation were excluded. Just over 2/3 of patients were dialysis-dependent on presentation. They found that treatment with PLEX had a better renal recovery (alive and off dialysis and SCr<500umol/L) at 3 months than IV steroids (70% vs 49% respectively, P=0.02). The HR for ESRD at 12 months for PLEX vs IV steroids was 0.47 (0.24-0.91, P=0.03). Survival however was not significantly different (19 deaths in PLEX group vs 16 in IV steroids group) and most deaths were due to infections (19), lung hemorrhage (6) or cardiovascular disease (4) and very few due to vasculitis. A sub-study of the MEPEX trial by Van Wingaarden et al found that for patients requiring dialysis on presentation and with severe tubular atrophy on biopsy, the point at which patients would get more benefit for renal survival from treatment over risk of death from treatment was when they had 18% or more normal glomeruli for IV steroids group as opposed to only 2% normal glomeruli for PLEX. This suggests that patients with most severe disease are more likely to reap renal benefit from treatment when they are given PLEX. In 2013, Walsh et al published the long term follow-up data from the MEPEX trial and found that the short term benefit seen in MEPEX was lost. Indeed, for patients treated with PLEX there was no significant improvement in the composite of ESRD or death (HR 0.81, 0.53-1.23; P=0.32) nor in the outcome of ESRD (0.64, 0.40-1.05; P=0.08). At final follow-up, half the patients died and 2/3 were either dead or on dialysis, reaffirming the poor prognosis of severe ANCA vasculitis. A meta-analysis of all randomized trials looking at PLEX for ANCA vasculitis by Walsh et al in 2011 found PLEX to be associated with a 20% risk reduction in the composite of ESRD-death (HR 0.80, 0.65-0.99) and a 36% reduction in ESRD (HR 0.64, 0.47-0.88) but no effect on death (RR 1.0, 0.71-1.42). The authors did warn though that overall most trials were small, none of them individually found a significant result for the composite of ESRD-death and they had notable methodological flaws such as randomization concealment was only performed in 4/9 trials and the methods of concealment weren’t described in any. Hopefully, the PEXIVAS study which is now nearing completion and should be presented at the upcoming ASN Kidney Week 2017 (hopefully as a late-breaking trial) will help clarify the role for PLEX in ANCA vasculitis. For now, it would seem that PLEX is indicated for patients presenting with severe renal failure due to ANCA-vasculitis as it improves renal survival, without a mortality benefit though.

Post-transplant FSGS

It is sad to say that there are unfortunately no other prospective trials studying the role of PLEX for glomerular disease. While the use of PLEX for recurring idiopathic FSGS post-transplant is recommended (the rationale being the removal of some as of yet unidentified pathogenic plasma permeability factor), the data is purely observational. A review of 77 case-reports and case-series, totalling 423 patients with recurrence of FSGS post renal transplant, published in BMC Nephrology in 2016 showed that overall 71% of patients achieved complete or partial remission. Factors most associated with response were male sex and starting treatment within 2 weeks of recurrence. However, the lack of control group prevents us from establishing a clear benefit from PLEX itself. Also, the treatment regimens were extremely varied and it is unclear exactly how much PLEX, for how long should it be given and which replacement fluid to use. Finally, the frequent use of PLEX in these patients who are already on immune-suppressing drugs may predispose to even more infections given the removal of Immunoglobulins by PLEX.

Atypical HUS

Similar to FSGS, the use of PLEX for atypical HUS is based purely on observational data (case reports and case series). The rationale behind its use for this indication certainly makes sense by removing defective complement factors and replacing properly functioning complement factors to halt the overactivity of the alternative pathway. Patients diagnosed with TMA are often started on PLEX promptly while awaiting results of diagnostic testing (Shiga toxin E. Coli cultures, ADAMSTS13 level and complement pathway factor levels and mutations). If diagnostic tests suggest an alternative complement pathway disease, it will be maintained until Eculizumab is available. Unfortunately, while most observational studies suggest an initial response around 60% to PLEX, this is mostly a hematologic response and patients will often become dialysis dependent.

Conclusion

Overall the evidence to support the use of PLEX for the treatment of glomerular diseases is not great. While anti-GBM disease and lung hemorrhage are considered some of the strongest indications for PLEX, this is not firmly supported by good prospective data. The best evidence is for its use is in severe ANCA-vasculitis and with the upcoming PEXIVAS study results hopefully this will further help us in our decision making. I think it is great that such a large study such as PEXIVAS (over 700 patients) for such a rare disease has been able to come to completion and this highlights the importance of proper collaboration to conduct prospective studies in GN. Hopefully this will inspire us to continue to strive for well-designed studies to guide us in the treatment of our patients.

David Massicotte-Azarniouch

Nephrology Fellow, University of Ottawa

World repercussion of the NEJM desensitization article – A Brazilian perspective

The recently published paper in the NEJM entitled “Survival Benefit with Kidney Transplants from HLA-Incompatible LiveDonors” caused a huge impact on Brazil’s media. Our main broadcast TV devoted few minutes explaining it, suggesting as a real breakthrough. Patients and many members of our multidisciplinary team were questioning if compatibility could be forgotten as a barrier to transplantation.

         Moved by this repercussion, on our weekly meeting we debated the article. Three questions were posed:

       1. Does transplanting HLAi patients really improve quality of life (life expectancy was shown to be expanded), compared to waiting on the list for a deceased donor?

       2. Why 5-year life expectancy for live donor kidney recipients in the US is 86% (USRDS data), while in the UK, Australia and at our own service it is around 97%. Does anyone has any suggestion of why such a huge difference?

       3. What about the high costs of desensitization? 

The former question is far from our reality. In our center, we do not perform HLAi transplants despite our high volume of over 900 kidney transplants per year. Due to low reimbursement, complications that may arise from HLAi transplants such as re-hospitalizations, requirement for additional plasmapheresis and IVIG as well as biopsies may significantly affect the cost of post-transplant care and prevent appropriate treatment of complications.

This cautious approach to cost is immensely influenced by our political and economical scenario. After chaotic administration and corruption, our GPD is falling ~3%. State health insurance is paying less than the actual cost for a dialysis session. In some centers, this is forcing doctors do reduce the dialysis session by 30 minutes (from 240 minutes to 210 minutes/session). In this context, proposing a new and costly treatment (like desensitization) that should be reimbursed by our Public Health System would sound as an outrage to the state health managers. Clearly, it seems the media has been over optimistic with the article conclusions. Many centers in the USA are actually favoring kidney paired exchange to minimize the complications and costs of desensitization. What do physicians from developing countries think about this? Additional comments are appreciated. 

Thiago Reis, MD

Hospital do Rim, UNIFESP, São Paulo, Brazil 

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 is 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)

Desensitization in kidney transplantation: a clear survival benefit

I would like to direct your attention to a landmark paper in transplantation just published on the NEJM two weeks ago.

We have previously discussed the terms used to characterize sensitized patients and the most common protocols to overcome this barrier to transplantation. Briefly, more than 30% of patients on the waiting list for a kidney transplant are sensitized to HLA antibodies, with more than 8,000 patients being highly sensitized. Sensitized patients have 3 options to undergo kidney tx:

- stay on the waiting list (hoping to get a matched kidney - annual transplantation is below 7%);
- enroll in a paired kidney donation (improves chances but still low rate); or
- undergo a desensitization protocol.

Desensitization usually involves plasmapheresis, IVIg and high dose immunosuppressive drugs (+/- rituximab) in order to decrease circulating anti-HLA antibodies. These patients have a high risk of complications, including bleeding, cancer, infection and antibody-mediated rejection (which is associated with poor allograft function). Moreover, these patients are very expensive to the hospital’s transplant program. More recently, with the spread of quality of measures in transplantation, having many sensitized patients on a program can significantly reduce the successful statistical outcomes of transplantation and consequently deteriorate the image of the program. Therefore, many programs just avoid taking highly sensitized patients.

Despite all the potential complications, whether undergoing desensitization leads to significant long-term survival benefit is unknown. Montgomery et al. analyzed a single-center cohort of 211 sensitized patients who underwent desensitization (IVIg+plasmapheresis) followed by renal transplantation, comparing with two carefully matched control groups of patients on a waiting list for kidney tx who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group). During the 11-year study period, 98% of the sensitized patients underwent successful transplantation and this study included patients with different detection methods of anti-HLA antibodies, such as positive cross-match by cytotoxicity assay, flow cytometry and/or bead assay (Luminex).

In the desensitized group, rates of survival were 90.6% at 1 year, 85.7% at 3 years and 80.6% at 8 years, compared with 91.1%, 67.2% and 30.5% in the dialysis-only group (view figure). Among the different levels of anti-HLA antibodies, patients with positive cross-match by cytotoxicity assay carried the worst outcome. Nonetheless, the survival benefit curve crossed at 18 months even in that group. Combining all sensitized groups, the survival benefit was clear after 12 months.

Overall, major adverse events during desensitization treatment occurred in less than 5% of patients, including anaphylaxis or bleeding. The most common cause of death was cardiovascular disease (~16% patients) and there were 6 deaths related to infection (~3%), which were likely secondary to the intensive immunosuppression produced by the desensitization protocol. In summary, sensitized patients can obtain a significant survival benefit by undergoing desensitization followed by kidney transplantation compared to alternative options, but risks of infection are higher and more studies are needed to help identify patients at greatest risk of dying and suffering from complications like malignancy or cardiovascular disease.

Plasma Exchange for Catastrophic Antiphospholipid Antibody Syndrome

Interesting case for the weekend: young woman with known lupus, baseline normal kidney function; admitted initially with headaches and "feeling more lupusy than usual", found to have a creatinine of 2.5 on admission with some dysmorphic RBCs on u/a and low complements. Presumed to have lupus nephritis and a biopsy was deferred for several days due to significant thrombocytopenia. When her Cr kept on increasing to the 5's & platelets had improved, a biopsy was eventually performed, and did NOT show lupus nephritis: instead, it showed rip-roaring thrombotic microangiopathy! The patient's lupus anticoagulant is positive, and we are now operating on the assumption that she has renal failure based on antiphospholipid antibody syndrome-induced TMA. How do we treat it?

Catastrophic Antiphospholipid Syndrome (CAPS) describes a rare subset (about 1%) of patients with APLAS who develop significant end-organ damage as a result of widespread thrombotic occlusion. It can cause kidney damage by virtue of thrombic microangiopathy. In addition to treatment with anticoagulants (e.g., coumadin) , steroids, and possibly IVIG, there is also a purported role for therapeutic plasma exchange. There is however a controversy as to what type of replacement fluid should be given: some believe that FFP should be used, as it contains "natural anticoagulants" which may help in treating the underlying condition, while other believe that albumin should be used, using the rationale that the clotting factors, cytokines, and complement activation products present in FFP could worsen the "thrombotic storm" driving the thrombotic microangiopathy. Although the numbers are small, current data seems to indicate that plasma exchange does help in the treatment of this condition with relatively high morbidity & mortality.

Empiric Management of Suspected RPGN

RPGN is a nephrologic emergency, and one of the more exciting consult cases for nephrologists to participate in.  Much like dealing with a stroke or heart attack, delays in initiating therapy can lead to substantially worsened outcomes.  Prompt initiation of therapy can be exceptionally challenging in RPGN, as even patients with advanced renal compromise may feel clinically well (as opposed to a stroke or a heart attack), and convincing them to accept aggressive therapies such as plasma exchange can be tough.  Furthermore, for patients who present acutely, we don't always have as much data as we would like to help make a decision.  Unfortunately, waiting for renal biopsy results or serologies to come back before making the decision to treat glomerulonephritis can result in costly delays.  

For this reason, any patient suspected of acute RPGN--defined as having an acutely elevated creatinine along with an active urine sediment--should be treated empirically. 

Most patients in this situation can be treated solely with a steroid pulse--e.g., Solu-Medrol 0.5-1 gm iv qd x 3 days--while waiting for serologies to come back and scheduling a renal biopsy.  

However, the presence of some specific clinical symptoms--pulmonary hemorrhage, CNS vasculitis, or mononeuritis multiplex--warrants a more aggressive empiric approach.  In addition to the steroid pulse, we typically initiate urgent plasma exchange and often consider beginning Cytoxan right off the bat.  

Plasma Exchange Nuts & Bolts

There are many indications for plasma exchange in nephrology:  some common ones include antibody-mediated rejection of a kidney transplant, Goodpasture's, ANCA-associated vasculitis, and TTP--all of which are commonly associated with loss of renal fellows' sleep--that is, you may very well be called upon to start plasma exchange in the middle of the night for one of these conditions.

There are two basic ways to achieve plasma exchange:  the Blood Bank Way (in which plasma is separated from blood cells using a centrifuge) and the Nephrology Way (in which a membrane plasma separator cartridge is installed within a dialysis machine circuit).  They both work, and which one gets the call appears to be highly center-specific.

Here's a quick-and-dirty guide to writing a plasma exchange order, realizing that specific circumstances may well alter what the final order will be:

1.  Estimate plasma volume (=.065 x weight in kg) x (1-Hct).

2.  Decide how many plasma volumes to remove (we typically use 1.5 plasma volumes, which ends up being between 40-60 cc/kg).

3.  Specify what the replacement solution will be:  you need to replace the plasma volume amount removed in a 1:1 fashion; a good default is using 2/3 volume of 5% albumin and 1/3 volume normal saline.  For example, if you remove 4 liters total, you could replace with 2.66 liters of albumin & 1.33 liters of normal saline.  You may have to use some FFP as well (for example, if the coags are elevated or you are doing plasma exchange for TTP).

4.  Specify calcium replacement:  usually 4-6 grams.

5.  Specify anticoagulation:  you can certainly try going it heparin-free, though in my limited experience clotting occurs more frequently than in dialysis.  A 2000 unit heparin bolus, if tolerated, is not a bad idea.

Plasma Exchange for Myeloma?

A question which comes up not infrequently during nephrology fellowship is whether or not to perform pheresis on patients with multiple myeloma. Once very much in vogue, the results of a fairly recent (Annals of Internal Medicine, 2005) randomized control trial cast doubt on the efficacy of plasma exchange in this group of patients, and it is not used with as much enthusaism (though I have certainly seen it done).

The trial was done on over 100 patients with newly-diagnosed myeloma and acute kidney injury who were randomly assigned to conventional therapy alone versus conventional therapy plus pheresis (5-7 treatments over 10 days). The end-point was a combination of death, dialysis-dependence, or GFR<30 at 6 months. The two groups did not show any significant difference though there was a slight “trend” (58% versus 69%) towards benefit in the pheresis group. Limitations of study were that there was no renal Bx performed and the numbers were small.

I myself am not in favor of pheresis for patients with myeloma. If I were to use it, I would do so only in conjunction with chemotherapy (the clearance of light chains by pheresis, which is actually pretty inefficient, provides a temporary effect only), and in patients with relatively high concentrations of serum & urine light chains. I would imagine that this treatment, like many in nephrology, would be much more effective early on in the course of renal involvement, and may have little effect on patients with advanced renal failure or those already on dialysis.

the MEPEX Trial

When you are called at 5pm to start pheresis on a patient with Wegener's granulomatosis who is already on dialysis...there is a certain part of the renal fellow which wants to say, "Come on--the dude is already on dialysis--what are we trying to save here?--my guess is that it's Game Over."

Well the results of the MEPEX trial would suggest otherwise. The trial was a randomized control trial in which 137 patients with ANCA-associated vasculitis and a serum Cr > 5.8mg/dL were randomized to receive either 7 sessions of plasma exchange over a 14 day period or Solu-Medrol 1000mg iv qd x 3d. In addition to these therapies, all patients also received prednisolone (1mg/kg/day, tapered over 6 months) + Cytoxan (2.5mg/kg/day x 3months) followed by Imuran for maintenance of remission.

Importantly, the plasma exchange arm was associated with an improved mortality and improved renal function (43 versus 19% risk of progression to ESRD at one year), and many of the patients in the pheresis arm were actually able to come off dialysis. The benefit was typically seen within the first 3 months of therapy, so many nephrologists will treat ANCA-associated vasculitis aggressively (e.g., pheresis, steroids, Cytoxan) for a good three months, and if they're still on dialysis to stop if there's no response.