Introduction and Background
A 46 y/o male with history antiphospholipid Abs on apixoban for DVT in 2012 was referred for renal failure and proteinuria. The patient was seen 9/17 with creatinine 1.6 mg/dl (1.1 in 1/16, 1.4 in 1/17), U/A 2+ protein, no blood, urine P/C ratio 146 mg/g. Serologic w/u normal including serum and urine immunofixation and serum free light chains (FLC): kappa FLC 45.6, lambda FLC 51.9 with a K/L FLC ratio of 0.9 (nl 0.37-3.1 in pts with renal insufficiency) https://tinyurl.com/yakoqt9d. A renal biopsy showed a mesangial proliferative GN with only IgG1 lambda by immunofluorescence consistent with “Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits” (PGNMID). The patient we seen by hematology and a bone marrow was nl including flow cytometry, fluorescence in situ hybridization (FISH), chromosomal studies and stains for amyloid.
PGNMID is an uncommon diagnosis, and without any evidence of a circulating paraprotein or cell clonality in the bone marrow, what is the pathophysiology of this lesion and how do we go about treating it?
While PGNMID is uncommon, the biopsy results are diagnostic. Two references were provided: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2736767/ a 2009 description from Columbia and the Ohio State of 37 patients, and a 2015 review on monoclonal gammopathy of renal significance (MGRS) from the International Kidney and Monoclonal Gammopathy Research Group https://www.ncbi.nlm.nih.gov/pubmed/25607108. One of the authors, Dr. Nelson Leung, has had extensive experience with MGRS and has been very active in ASN Communities, so the Community leaders went directly to him. He made these important points about PGNMID in general and specifically for this case:
- Patients with PGNMID and monoclonal IgG1 deposits are more likely to have a detectable circulating monoclonal protein than those with the other IgG subclasses. However, not all do as it appears to be the case here. However, there may be a clue in this patient’s serum FLCs. Both kappa and lambda are elevated (which is normal for a reduced GFR) but in pure renal insufficiency, kappa should be significantly higher than lambda. With the reverse happening in this patient (K/L FLC ratio 0.9) it supports a circulating lambda monoclonal protein.
An important point about this case is that even though there is no definitive evidence of a circulating monoclonal protein or clonal cell line, the immunoglobulin restriction in the kidney is evidence of their existence. The assumption is that there is a clone that is indeed producing a circulating monoclonal protein that is depositing in the kidney, but both are at levels that are simply too low for present techniques to detect.
- This patient is losing renal function and needs to be treated. Treatment should be targeted to the specific clonal cell line if one is identified. The problem is, what do you treat with when you don’t know what cell line is responsible, as is the case here? We are used to thinking of MGRS as plasma cell dyscrasias that are typically treated with a proteasome inhibitor such as bortezomib. However, lymphocytic clones that express CD20 can also produce these monoclonal proteins and they will not respond to bortezomib, but can be targeted with rituximab. Similarly, plasma cells do not express CD20 and will not respond to rituximab. Dr. Leung quoted his experience in which a cell line could be detected (n=10) and 50% were plasma cells and 50% expressed CD20. He mentioned another series from U of Pennsylvania in which 7 cases were identified and similarly 3 of the 7 were plasma cell related.
- Given that this there is a 50/50 chance of picking the cell line, what should we start treatment with and what should we follow? Dr. Leung starts with rituximab for purely practical reasons; he finds it easier to get approval for rituximab than bortezomib. He gives 8 weekly rituximab treatments and follows the patient’s proteinuria. In this case if the patient’s IgG1 level was elevated in the blood, he would follow that too. He uses 8 weekly doses because lymphoplasmacytic clones (responsible for Waldenstrom macroglobulinemia) have a slow response time, and he feels by 8 weeks, if an appreciable response has not been seen, that it may be reasonable to switch to bortezomib.
Even though there was no evidence of a clonal cell line or a circulating monoclonal protein in this patient, the IgG1-lambda restriction in this case identified it as a MRGS and given that there was mesangial proliferation, and the absence of amyloid etc, this case qualified for the diagnosis of PGNMID. Treatment should target the clonal cell line if one can be identified: bortezomib for plasma cells, or rituximab for lymphocytes. If a clonal line cannot be identified, then is seems reasonable to pick one and if no response is seen, to proceed to the other.