Curing Cast Nephropathy by Removing Not-so-light Chains?

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Tuesday, Dec 19, 2017,  9 pm Eastern

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JAMA. 2017 Dec 5;318(21):2099-2110. doi: 10.1001/jama.2017.17924.

Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis IndependenceAmong Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial.

Bridoux F, Carron PL, Pegourie B, Alamartine E, Augeul-Meunier K, Karras A, Joly B, Peraldi MN, Arnulf B, Vigneau C, Lamy T, Wynckel A, Kolb B, Royer B, Rabot N, Benboubker L, Combe C, Jaccard A, Moulin B, Knebelmann B, Chevret S, Fermand JP; MYRE Study Group.

PMID: 29209721  Full text at JAMA (free till Dec 21)

Editorial by Kenar Jhaveri and Ruben Niesvizky 

Renal Fellow Network blog post (from 2013) by Paul Phelan

Introduction

Multiple myeloma (MM) is a clonal plasma cell malignancy that accounts for approximately 10% of hematologic malignancies. The annual incidence, age-adjusted to the 2000 United States population, is 4.3 per 100,000, resulting in over 20,000 new patients in the United States each year. MM is twice as common in blacks compared to whites. There is a slight male predominance as well. The median age of onset is 66 years. Only 2% of patients are less than 40 years of age at diagnosis.

The most common presenting symptoms of MM are fatigue and bone pain. Anemia occurs in 75% of patients. Osteolytic skeletal lesions are found detected in 80% of patients. Other common findings at presentation include hypercalcemia (15%), and elevated serum creatinine ≥2 mg/dL (20%).

Normally, the kidneys filter less than one gram of polyclonal light chains per day, which are subsequently catabolized by the proximal tubule cells. In multiple myeloma, the kidneys filter 80+ grams of pathogenic monoclonal light chains (Bence–Jones proteins). Excessive endocytosis of light chains by proximal tubule cells triggers apoptotic, pro-inflammatory, and fibrotic pathways. Light chains are subsequently delivered to the distal tubule and form casts by binding with Tamm–Horsfall protein (THP), which is produced in the thick ascending limb of the loop of Henle. Casts cause intratubular obstruction, interstitial inflammation and fibrosis. These changes reduce tubular flow and increase the exposure of the tubule to high single-nephron light chain concentrations. Nearly 50% of patients with multiple myeloma develop renal disease; acute kidney injury (AKI) from cast nephropathy, or "myeloma kidney", is the most common type.

This study sought to find out if high-cutoff hemodialysis (allowing efficient serum immunoglobulin light chain removal through very large membrane pores) improve kidney function in patients with myeloma cast nephropathy and severe acute kidney injury?

Why high-cut off dialysis, and how does this work?

Dialysis itself is not enough to remove light chains - their size is too large (kappa and lambda light chains have molecular weights of 22kD and 45kD respectively) for conventional - even high flux dialysis. Plasmapheresis has been tested, and found not to be efficacious. High cut-off dialysis uses a different dialysis filter, with larger pore size (see this PDF link for the manufacturer information) allowing removal of molecules up to 45-50 kDa. Though albumin is larger (66.5 kDa) albumin loss is greater than with high flux dialysers. Given that removal of light chains, like middle molecules, would depend more on convection more than diffusion, the main determinants of their clearance are pore size, surface area and time - and not so much blood flow and dialysate flow as for diffusion. Case reports and case series suggested that resolution of cast nephropathy could follow removal of light chains, hence this randomized trial. 

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Methods

Randomized clinical trial with 98 patients with biopsy-proven myeloma cast nephropathy requiring hemodialysis treated at 48 French centers between July 2011 and June 2016. The high cutoff dialysis is one part of the study (among patients needing dialysis); another was bortezomib plus dexamethasone (BD), compared with cyclophosphamide plus bortezomib and dexamethasone (C-BD), in patients not requiring hemodialysis.

Inclusion criteria:

  • Diagnosis of secreting multiple myeloma (according to criteria from the International  Myeloma Working Group)
  • Biopsy-proven cast nephropathy
  • Clinical indication for hemodialysis
  • Neutrophil counts of 1.0 × 109/L or greater and platelet counts of 70 × 10^9/L or greater

Exclusion criteria:

  • Pre-existing chronic kidney disease with an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m^2 for longer than 3 months
  • Previous course of chemotherapy for myeloma
  • Uncontrolled malignant disorder, infection, or peripheral neuropathy
  • Associated immunoglobulin light chain amyloidosis in the kidney or overt light chain deposition disease with nodular glomerulosclerosis

Interventions

  • Intensive hemodialysis (eight 5-hour sessions over 10 days) with either a high-cutoff dialyzer (the Gambro Theralite 2.1 m^2)

OR

  • High-flux dialyzer.

All patients received the same chemotherapy regimen of 21-day cycles with bortezomib (1.3 mg/m^2 on days 1, 4, 8, and 11) and dexamethasone (20 mg on days 1-2, 4-5, 8-9, and 11-12).

Outcomes

Primary endpoint was hemodialysis independence at 3 months (defined by an eGFR ≥15 mL/min/1.73 m2 15 days after the last hemodialysis session)  

Secondary endpoints included hemodialysis independence rates at 6 and 12 months, complete recovery of kidney function (defined by return to baseline level of serum creatinine or eGFR if known or by eGFR ≥60 mL/min/1.73 m^2 at 6 months and 12 months), hemodialysis- and chemotherapy-related adverse events, and death.

Analytic Plan

The analyses were performed on a modified intention-to-treat basis. 

The χ2 test was used to compare hemodialysis independence at 3, 6, and 12 months and event-free survival at 12 months.

For sample size estimation, the assumption was a 30% hemodialysis independence at 3 months (based on prior literature) and an improvement on that number by 60% with high cutoff hemodialysis. 

A secondary analysis used a mixed-effects logistic model to account for potential center effects. Center effects were accounted for in the post hoc analysis using a random-effects estimator that compares the change in the odds for a treated patient vs a control patient from the same center.

Funding Information

The study was funded by the  French Ministry of Health, French National Hospital Program for Clinical Research Cancer, 2009. Gambro provided the high-cutoff dialyzers used in the study, and Janssen France provided bortezomib. 

Results

Among 98 randomized patients, 94 (96%) were included in the modified intent-to-treat analysis. See figure 1 and table 1 for the details

Figure 1 from Bridoux et al, JAMA 2017

Figure 1 from Bridoux et al, JAMA 2017

Table 1 from Bridoux et al JAMA 2017

Table 1 from Bridoux et al JAMA 2017

Primary Outcome and Secondary Outcomes

Table 2 from Bridoux et al, JAMA 2017

Table 2 from Bridoux et al, JAMA 2017

As can be seen, hemodialysis independence in the control group was 33%, very close to the sample size assumption of 30%. However, the difference in primary outcome occurred only in 3 additional patients, ie 8% percent, thus the difference was not significant.

Figure 2 from Bridoux et al, JAMA 2017

Figure 2 from Bridoux et al, JAMA 2017

Figure 2 A shows the cumulative incidence of hemodialysis independence within 12 months after randomization. As also apparent from table 2, the 12-month estimate was 60.9% (95% CI, 47.0%-74.8%) in the high-cutoff hemodialysis group and 38.4% (95% CI, 24.5%-52.2%) in the conventional hemodialysis group (P = .04). Hemodialysis independence occurred after a median of 2 months in the high-cutoff hemodialysis group and after a median of 1 month in the conventional hemodialysis group. Thus, though the 3 month difference was not significant, there seemed to be a separation with longer follow up. 

Event-Free and Overall Survival

At 12 months, among 75 patients, 41 were still alive and no longer receiving hemodialysis (24/37 [64.9%] in the high-cutoff hemodialysis group and 17/38 [44.7%] in the conventional hemodialysis group; between-group difference, 20.2% [95% CI, −2.6% to 42.9%]; OR, 2.28 [95% CI, 0.90 to 5.77]; P = .15) and had median eGFR values of 36 mL/min/1.73 m2 (IQR, 25 to 63 mL/min/1.73 m2) and 39 mL/min/1.73 m2 (IQR, 27 to 53 mL/min/1.73 m2), respectively.  

Figure 2 B above shows overall survival, within a median follow-up of 17.5 months (IQR, 12.0-30.0 months), 29 patients had died (13 in the high-cutoff hemodialysis group and 16 in the conventional hemodialysis group; HR, 0.76 [95% CI, 0.36-1.58]; log-rank test P = .46;

Chemotherapy and Hematologic Response 

The median time from diagnosis of AKI to initiation of bortezomib was 8.0 days (IQR, 5.0-12.0 days) in the high-cutoff hemodialysis group and 9.0 days (IQR, 5.5-13.0 days) in the conventional hemodialysis group. Forty patients in each group received at least 3 courses of bortezomib and dexamethasone. Cyclophosphamide was added for 13 patients (28%) in the high-cutoff hemodialysis group after a mean of 4.4 months (SD, 1.0 month) and for 11 patients (23%) in the conventional hemodialysis group after a mean of 4.2 months (SD, 0.6 months). Incidentally, autologous stem cell transplantation was performed in 13 patients in the high-cutoff hemodialysis group and in 6 patients in the conventional hemodialysis group. 

Hemodialysis Procedures

Table 2 also shows that compared to standard membranes, the membrane used for patients in the high-cutoff hemodialysis group did produce a significantly higher reduction of both κ and λ light chain levels after the first and third hemodialysis session (P < .001).  

Variables Associated With Kidney Outcome

The bivariable analysis of the variables associated with hemodialysis independence within 12 months appears in Table 3. The main variables were whole immunoglobulin–secreting myeloma, involved serum-free light chain level of 500 mg/L or less after 1 cycle of chemotherapy, and randomization to the high-cutoff hemodialysis group.

Table 3 from Bridoux et al, JAMA 2017

Table 3 from Bridoux et al, JAMA 2017

Adverse events

Though overall there was no difference between the two arms for adverse events, the need for albumin infusions for low albumin levels (< 2 g/dL) was higher in the high cutoff group (41% vs 4%). 

Conclusion

Among patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, the use of high-cutoff hemodialysis compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis independence at 3 months.  However, among the secondary end points, more patients in the high-cutoff group vs the conventional group no longer required hemodialysis at 6 months (56.5% vs 35.4%, respectively; P = .04) and at 12 months (60.9% vs 37.5%; P = .02). In addition, the overall hematologic response rate at 3 months was higher at 89.1% in the high-cutoff group vs 62.5% in the conventional group (P = .003). There was no difference in mortality at 12 months.

Limitations  

The authors acknowledge that the study had a least four limitations: underpowered study, potential type I error, inflation of type I error rate and choice of treatment regimen (i.e. use of a bortezomib-dexamethasone doublet instead of a triplet).  

Additional points to consider for discussion

  • Four patients were excluded from analysis in the intervention arm, 3 since they did not have cast nephropathy. This occurred despite the inclusion criteria of cast nephropathy - and no further details are available of how this happened - important given the small numbers. 
  • How would one explain the improvement in hematologic response with high cut-off hemodialysis as seen in table 2? Why should the bone marrow respond to light chain removal?
  • The elephant in the room - EULITE, which was presented at UK Kidney week in 2016, despite a more intensive strategy did not report a benefit in renal outcomes and a worse overall survival - and which has still not been published yet. See this for a comparison of the two trials from an editorial in the Journal of Onconephrology by Kevin Finkel and Paolo Fabbrini
Table from Finkel et al, JON, 2017

Table from Finkel et al, JON, 2017

Summary by Scherly Leon, Nephrologist, New York