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Efficient B cell Depletion With Rituximab Despite Massive Proteinuria

Halfon, Matthieu MD1; Pascual, Manuel MD1; Aubert, Vincent PhD2; Rotman, Samuel MD3; Yannick, Muller D. MD, PhD1

doi: 10.1097/TP.0000000000002352
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1 Transplantation Center, Lausanne University Hospital, Lausanne, Switzerland.

2 Service of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland.

3 Service of Clinical Pathology, Lausanne University Hospital, Lausanne, Switzerland.

Received 10 May 2018. Revision received 21 June 2018.

Accepted 23 June 2018.

M.H. and M.D.Y. collected the data and wrote the article. M.P. wrote the article. V.A. performed the biological drugs analysis. S.R. performed the histological analysis.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal.

Research involving animal or human subjects: the following case report was exempt from approval from an ethics' board.

The authors have no financial disclosure or any conflicts of interest. Y.D.M. was supported by the Swiss National Research Fund (grant P300PB_174500).

Correspondence: Matthieu Halfon, MD, Rue du Bugnon 44, Transplantation Center, CHUV, 1011, Lausanne, Switzerland. (Matthieu.Halfon@chuv.ch.).

Since the RAVE and the RITUXVAS trials, the use of rituximab (RTX), an IgG1 anti-CD20 monoclonal antibody, has significantly increased and is currently recommended as first line therapy in various types of glomerulonephritis.1 To date, the minimal dose of RTX to induce significant and durable B cell depletion remains unknown. Furthermore, the efficacy of RTX remains controversial in nephrotic patients, the drug being potentially excreted and lost in the urine.

We report a 43-year-old recipient with anuric end-stage renal disease due to primary focal and segmental glomerulosclerosis (FSGS), who underwent kidney allograft transplantation from a deceased donor. The induction regimen consisted of 2 doses of basiliximab, cyclosporine, methylprednisolone, and mycophenolate mofetil. On postoperative day 1, the proteinuria-to-creatinine and albumin-to-creatinine ratios increased, respectively, from 395 and 271 g/mol to 1111 and 993 g/mol (Figure 1A). Recurrence of primary FSGS was suspected, and the patient received daily plasma exchanges and high-dose cyclosporine (plasma levels, 250-400 μg/L). A kidney biopsy confirmed recurrent FSGS, showing diffuse foot process effacements without evidence for cellular or humoral rejection (Figure 1B).

FIGURE 1

FIGURE 1

One month later, the clinical outcome remained unfavorable with increasing proteinuria, and the decision was made to additionally administer rituximab (RTX) 375 mg/m2 twice (700 mg/injection) at 7-day interval, as RTX has been shown to target podocytes in FSGS.2 No trace of RTX was detected in serum or in the 24-hour urine collection after the first injection. The serum concentration of RTX 48 hours after the second injection was 118 mg/L. The 24-hour urinary excretion of RTX were 43.7 and 29.7 mg, respectively, in the first and second days after the second infusion (Figure 1C). The excretion fraction of RTX and immunoglobulin G (IgG) were 0.65% and 1.3%, respectively. Peripheral CD20+ B cells were efficiently depleted (Figure 1D), although clinical remission was not achieved.

Previous reports have suggested that RTX is less effective in nephrotic patients compared with non-nephrotic patients because of loss in the urine and lower plasmatic levels of RTX.3 Indeed, podocyte foot process fusions are associated with overfiltration of serum proteins, which leads to loss of albumin (molecular weight, 65 kDa), immunoglobulin G (molecular weight, 150 kDa) and possibly also RTX (molecular weight, 142 kDa). We found that RTX was only partly excreted in the urine with significant (>100 mg/L) plasmatic levels of RTX detectable and complete B cell depletion, possibly due to the high affinity of RTX for CD20 and preferential excretion of lower molecular weight proteins than RTX, as suggested by the IgG and albumin serum-to-urinary ratios (4.5 and 2.25, respectively). Recent evidence showed that the degree of B cell depletion positively correlated with clinical response and inversely with the level of RTX in several autoimmune diseases.4 Altogether, these data emphasize the potential benefit for monitoring B cell counts and RTX plasmatic levels over time to better define the right dosing and timing interval between each infusion in nephrotic patients.

In conclusion, administration of 2 weekly 375 mg/m2 doses was efficacious to deplete circulating CD20+ cells. More studies analyzing RTX use in nephrotic patients are needed before recommendation can be proposed.

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REFERENCES

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4. Md Yusof MY, Shaw D, El-Sherbiny YM, et al. Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus. Ann Rhuem Dis. 2017;76:1829–1836.
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