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.

The potential danger in treating Hypothermia-induced Hypokalemia

The post from Veeraish earlier this week reminded me of this patient who demonstrated an important learning point regarding hypokalemia in hypothermic patients. A 75 year old woman was found unconscious in her unheated home with overnight temperatures of -1⁰C. On arrival at the Emergency Department, her core rectal temperature was a staggering 21⁰C, blood pressure 90/50 and pulse was 28 beats per minute. EKG was classic, demonstrating slow atrial fibrillation, wide T wave inversion and the characteristic J waves of hypothermia (see Figure; note that the depth of the J wave inflection correlates with the degree of hypothermia). Laboratory values included  serum potassium of 1.1 mmol/L, phosphorous <1 mg/dl, pH 6.95, lactate 8.5 mmol/L, glucose 522 mg/dl. Her renal function was normal. After some initial warming, repeat potassium was 1.6 mmol/L and her heart rate improved. When she had been warmed to 26⁰C, the serum potassium corrected to 5.1 mmol/L before settling at 3.6 mmol/L (with no potassium supplementation). Her serum phosphorous level and blood sugars normalized when her body temperature rose above 30⁰C. She also spontaneously converted to sinus rhythm. 

This case illustrates the profound metabolic complications which can arise in the context of extreme hypothermia. Hypokalemia is well recognized in hypothermia, however, the drop in serum potassium levels is usually mild. Most reported cases involve intentional body cooling in treatment of severe head injury or post-cardiac arrest. The mechanism of hypokalemia is thought to be redistribution of potassium back into the cell. As mentioned by Veeraish, a case has been bravely described of a patient developing hypothermia-associated hypokalemia while being intentionally cooled after head injury. Treatment with potassium supplementation and re-warming occurred concurrently and the patient then suffered a fatal arrhythmia. As the serum potassium will correct itself with rewarming, we should be extremely cautious about administering potassium to hypothermic patients due to the risk of severe rebound hyperkalemia.

Extended High Cut-Off (HCO) Hemodialysis for Myeloma Cast Nephropathy

There has been much recent interest in novel extra-corporeal treatments for removal of nephrotoxic free light chains (FLC) in myeloma cast nephropathy. HCO dialyzers employ high flux membranes with particularly large pores (up to 50kDa Vs 15kDa for conventional high flux) facilitating the removal of large plasma proteins such as FLC (kappa and lambda light chains have molecular weights of 22kD and 45kD respectively). HCO-HD may also be potentially beneficial in rhabdomyolysis with myoglobin having a molecular weight of 17kDa.

Extra-corporeal removal has primarily been achieved using plasma exchange and has long been a controversial topic in nephrology. HCO dialyzers are much more efficient at clearing FLC compared to plasma exchange. Multiple case reports have suggested a benefit to early use of HCO-HD in cases of cast nephropathy and a study by Hutchinson CA et al demonstrated an early reduction in FLC to be associated with renal recovery. Another paper from the same group reported on 67 patients with AKI due to cast nephropathy who received HCO-HD with modern chemotherapy. The majority of patients had sustained reductions in serum FLC concentrations (76%) and a high rate of independence of dialysis (63%). The HD regime used Gambro HCO 1100 dialyzers and was aggressive, with almost daily 8-hour sessions for the 12 days. After this, the schedule drops back to alternate days and finally to three 6-hour sessions per week after day 21. My limited experience with this regime in 2 patients demonstrated a need for regular phosphate and albumin repletion and careful monitoring of other electrolytes.

Obviously HCO-HD will only remove FLC and will not stop their production. Therefore, for a sustained response, patients need to be a on a chemo-sensitive regime. The above studies have demonstrated that patients who need a break in chemotherapy do worse, as do those with signs of chronicity on renal biopsy.

The following criteria are suggested before considering HCO-HD in patients with AKI due to cast nephropathy:

1.       Chemo-sensitive regime; bortezomib is frequently employed

2.       High serum FLC levels (>500mg/l; usually much higher)

3.      Low levels of interstitial fibrosis & tubular dropout on biopsy (i.e. evidence of salvageable kidneys)

A randomized controlled trial, led by Dr. Hutchinson, in the UK is currently on-going (Eulite Trial) which will compare conventional high flux HD with HCO-HD in patients receiving chemotherapy (bortezomib or thalidomide plus dexamethasone). HCO-HD certainly appears to be more efficient than plasma exchange at reducing FLC levels but at this point, its precise role in the management of cast nephropathy is unclear. We await the Eulite trial to hopefully clarify the potential benefit of HCO dialysis in this situation.