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Written by: Krithika Mohan, MD
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
The spectrum of monoclonal deposition diseases has expanded over the past 3 decades, of which the most recent addition is proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID). It was first described in 2004 by Nasr et al as a distinct entity which could not be assigned to the previously established categories of glomerular involvement by dysproteinemia. Deposition of M protein in the glomerulus causing inflammation secondary to complement activation is the most widely accepted pathogenesis of PGNMID. The culprit is most often IgG3κ which is nephritogenic- due to its high molecular weight and anionic charge. The mechanism of M protein production is believed to be from 2 mechanisms -
Abnormal immunoglobulins secreted by malignant B cells (typically monoclonal) or plasma cells in the bone marrow and/or serum in large quantities or
Abnormal immunoglobulins secreted by normal B cells or plasma cells (due to various factors such as infections, solid organ tumors and other unknown factors)
Patients with PGNMID are usually in their 6 th decade and may present with nephrotic range proteinuria, hematuria and/or decreased GFR. Low positive detection rate (<30%) of M protein in PGNMID makes diagnosis difficult. This low detection rate does not correlate with the severity of kidney disease. With treatment, around 30% of the patients have partial or complete recovery, 30% have persistent CKD and 20% progress to end stage kidney disease. Prognosis depends on creatinine level and degree of glomerulosclerosis and interstitial fibrosis at presentation.
PGNMID diagnostic criteria:
Light microscopy: proliferative or membranoproliferative glomerular pattern characterized by endocapillary and mesangial hypercellularity with lobular configuration and basement membrane double contours.
Immunofluorescence (IF): glomerular monotypic deposits (glomerular positivity for a single immunoglobulin class, a single IgG subclass in the case of IgG PGNMID and a single light chain isotype), usually IgG3
Electron microscopy: predominantly granular electron dense deposits in mesangial, subendothelial and/or subepithelial locations
Clinical: absence of clinical or laboratory evidence of cryoglobulinemia (PGNMID mimics immunotactoid GN and type 1 cryoglobulinemic GN in its clinical characteristics and course)
Evaluation of PGNMID requires thorough work up to for hematological malignancies, infections like parvo virus, hepatitis c and autoimmune diseases. The etiology of PGNMID is divided into two categories: primary hematologic diseases and others. Based on the hematologic assessment, primary hematologic-related PGNMID can be further divided into malignancy-related and MGRS-related PGNMID.
Figure 1- Clinical classification, etiology and evaluation of PGNMID
Existing treatment modalities in PGNMID
Treatment strategies of PGNMID are based on data derived from small cohorts and are not standardized. Choice of treatment depends on the cause, renal function and co-existing conditions. For example, a patient presenting with stable CKD 1 or 2 may be treated with RAAS blockade alone. Patients with rapidly declining renal function, and/or nephritic or nephrotic syndrome, warrant aggressive treatment including chemotherapy or immunomodulatory drugs. In those with advanced CKD who are not candidates for kidney transplantation, chemotherapy is not indicated. The goal of treatment is to preserve kidney function and improve quality of life while minimizing adverse effects. Responses to treatment are measured primarily by assessing the renal response, since there is often no underlying clonal disorder to track. A renal response includes 50% reduction in proteinuria, hematuria and improvement or stabilization of kidney function.
Drugs that have been used with variable success include (Table 1)
RAAS blockade
Steroids
Cyclophosphamide
Rituximab (RTX)
Bortezomib (BD)
Thalidomide, Lenalidomide
Daratumumab
To date, most studies have used empirical treatment of PGNMID due to lack of detectable clones, which makes therapeutic specificity and gauging treatment effect challenging. Immunomodulatory drugs (IMiD) like thalidomide or lenalidomide are now utilized as clone directed therapy, similar to their use in the treatment of myeloma.
The mechanism by which these medications work is depicted in figure below. In summary, IMiDs inhibit IL-6, TNF-alpha, VEGF/bFGF, cell growth and enhance T cell activation, increasing production of NK cells which in turn cause cell death.
Figure 2- Mechanism of action of IMiDs
In a small retrospective case series, a clone-directed approach was utilized. In this series, treatment was either directed at the underlying clone or, for patients without a detectable clone, treatment was empirically prescribed to target the hypothesized underlying clone. Interestingly, the renal response rate was 88%, and 38% demonstrated a complete renal response (proteinuria <500mg/24 hours). Additionally, all patients were free of ESRD at follow-up (median 693 days from diagnosis) and treatment was well tolerated.
Table 1. PGNMID therapies to date.
This brings us to the present study: Efficacy of Immunomodulatory Drugs in Combination With Dexamethasone in Proliferative Glomerulonephritis With Monoclonal Immunoglobulin Deposits.
This was a single center, retrospective study that included 64 patients with biopsy proven PGNMID. Visual abstract by @DTomacruzMD .
Exclusion criteria included patients with:
Cryoglobulinemia
PGNMID after renal transplant
Malignant hematological disease
eGFR <15 at time of biopsy
Lost to follow up
The 64 patients were divided into 3 treatment groups that received steroids, IMiD or BD/RTX as seen in figure 3.
Figure 3. Process of inclusion
Treatment protocols:
Steroid Group (n= 26)
Prednisone with or without RAAS blockade.
Dose - 0.5 to 1 mg/kg/d (max of 60 to 80 mg/d) for 4 to 8 weeks.
If effective, dose was reduced by 2.5 - 5.0 mg every 2 to 4 weeks to a long-term maintenance dose (5 mg/d) otherwise gradually tapered and stopped.
IMiD Group (n = 28)
Thalidomide and dexamethasone (TD) or lenalidomide and dexamethasone (RD).
TD- Initial dose of 100 mg/d thalidomide and 40 mg/week dexamethasone. TD Increased gradually to a maximum dose of 200 mg/night thalidomide if no obvious adverse reactions. No renal dose modification needed.
RD- Lenalidomide was given for 21 days and stopped for 7 days, and dexamethasone (40 mg/week) was given on days 1, 8, 15, and 22. Lenalidomide dose was adjusted according to renal function.
BD/RTX Groups (n = 10)
Rituximab: 375 mg/m2 was given once every 3 months.
Bortezomib: 1.3 mg/m2 bortezomib and 40 mg/d dexamethasone was given once a week for 4 weeks for 1 treatment cycle.
Renal remission was defined as
Complete remission (CR)- urinary protein ≤0.5 g/d, and stable renal function (±25%).
Partial remission (PR)- if urine protein level decreased by > 50%(if patient had nephrotic range proteinuria, then proteinuria was required to be decreased to < 3.5 g/d, and renal function was required to remain stable (±25%)).
No response - neither CR nor PR was achieved.
Relapse- worsening SCr or proteinuria levels in the kidneys after a PR or CR.
The endpoint was defined as 30% decline in eGFR or end-stage renal disease.
Results
Median follow up was 20 months (IQR 10-37 months).
Median urine protein level was 3.65 (IQR, 2.21–6.35) g/24h.
Median eGFR rate was 60 (IQR, 45–89) ml/min per 1.73 m2.
Rate of M protein detection was lower in the steroid group compared to the other 2 groups.
Other baseline characteristics were comparable in the 3 groups.
During the treatment period, 42%, 64% and 60% patients achieved renal remission in the steroid, IMiD and BD/RTX groups respectively. The complete renal remission rate in the IMiD group was significantly higher than that in the steroid group (53% vs. 23%, P = 0.022). The remission rates in the IMiD group and BD/RTX group did not significantly differ. The rates of relapse in the steroid group were also significantly higher than those in the IMiD group (P < 0.001) and BD/RTX group (P = 0.04). Hematological remission was seen in only 2 of the 64 patients.
Table 2. Renal and hematologic remission in the different groups
Renal remission at last follow-up was highest in the IMiD group (64%) and BD/RTX (60%) as compared to the steroid group (19%).
Figure 4. Renal remission rates in NR (no response), PR (partial remission), CR (complete remission)
Patients with low C3, IMiD, and BD/RTX protocols were more likely to achieve renal remission (P < 0.05) while those with hypertension and a creatinine of >1.24 mg/dl were less likely.
There were no significant differences in renal survival among the 3 groups as seen in figure 5. The renal prognosis of patients in the clone-directed treatment group (IMiDs and BD/RTX) was better than that of patients in the steroid group, but not statistically significant.
Figure 5. Renal survival analysis of patients in different groups through study endpoint.
As illustrated below, the incidence rates of severe adverse events were 23%, 46% and 60% in the steroid, IMiD and BD/RTX groups, respectively. In most patients, adverse reactions improved after the dose reduction. In fact, 47% of patients treated with thalidomide required a dose reduction because of adverse events.
Table 3. Comparison of severe adverse events among different treatment groups
This study showed that IMiDs in combination with steroids are effective in treating PGNMID with a renal response of nearly 60%. A similar response was not observed in older studies. This may have been because the study cohort had better renal function at baseline, and only mild IF at start of therapy. Low C3 levels, which are suggestive of alternative pathway involvement, was associated with better renal response. The association with low Ce levels was more obvious in the clone directed regimens - the IMiD and BD/RTX groups. The most common adverse effects of IMiDs were peripheral neuropathy and anemia. An effort to minimize this was made by starting low dose therapy and then gradually increasing the dose depending upon the patient’s response. Despite this, adverse effects to thalidomide were high, which makes this an important limitation. Patient tolerance of therapy was further decreased in patients with low estimated GFR. Although Bortezomib and daratumumab have fewer adverse effects, affordability is a major concern especially in low income countries.
This is the first study to report therapeutic remission with IMiDs in combination with steroids in patients with PGNMID. It is also the largest cohort, and longest follow up period in patients diagnosed with PGNMID to date. An important drawback is that it was a single center and retrospective study. Additionally, the BD/RTX group was a much smaller cohort compared to the IMid/steroid groups. Furthermore, the study follow-up time was inadequate to predict the long-term prognosis or effect and efficacy of these drugs in patients with PGNMID.
Despite these limitations, it may be worthwhile to consider the use of the IMiDs- steroid combination in a selected cohort of PGNMID patients, specifically those with better kidney function at presentation.
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
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