C3 glomerulonephritis associated with monoclonal gammopathy of renal significance: a diagnostic and therapeutic challenge

Introduction

Monoclonal gammopathy of renal significance (MGRS) is the term used to describe hematological conditions in which the production and secretion of a monoclonal immunoglobulin (mIg) causes kidney damage¹. These hematological disorders do not meet diagnostic criteria for multiple myeloma or lymphoproliferative disease and thus do not meet the previously defined hematological criteria for targeted treatment¹.

The spectrum of MGRS-associated kidney diseases is very broad, and kidney injury can be directly caused by the deposition of the monoclonal protein or less commonly through dysregulation of the complement alternative pathway (AP)¹,²,³. In this indirect mechanism, the monoclonal Ig acts as an autoantibody, activating AP through the inhibition of complement regulatory proteins, and there are no Ig deposits in the renal tissue¹,³. The best example of a MGRS-associated disorder with absent or scant monoclonal Ig deposition is C3 glomerulopathy (C3G), including dense deposit disease (DDD) and C3 glomerulonephritis (C3GN)¹.

Although C3G is a rare entity, several studies have shown a high prevalence of monoclonal gammopathy in patients older than 50 years with C3 glomerulopathy (reaching 65% in some series)⁴, much higher than the prevalence of monoclonal gammopathy in the general population (4.2%)⁵,⁶.

C3G is a histopathological diagnosis, characterized by dominant C3 deposition on immunofluorescent staining. Presentation is variable, ranging from asymptomatic hematuria to rapidly progressive glomerulonephritis⁷.

Currently, there is still some uncertainty regarding the best treatment for patients with mIg–C3GN. However, evidence from few case series and case reports suggests that myeloma-directed therapies are associated with improved renal outcomes compared to conservative or conventional immunosuppressive therapies⁴,⁸,⁹.

This case report describes the clinical course and outcomes of a patient with C3GN-associated MGRS treated with clone-directed therapy.

Case Report

A 61-year-old man with history of heart failure (LVEF 46%) after two hospitalizations for myopericarditis with cardiogenic shock in 2018 and 2021. Myocardial biopsy was performed in 2018 showing a discrete, non-specific lymphocytic infiltrate. There was no evidence of immune or neoplastic etiology, and a diagnosis of viral myopericarditis was assumed. He had an IgG/kappa monoclonal gammopathy of undetermined significance (MGUS) diagnosed in 2021 (M-spike of 0.38 g/dL on serum protein electrophoresis/ immunofixation and free light chain ratio kappa/lambda of 5.47).

In January 2022, he presented with erythrocyturia 25-50/hpf, proteinuria 2.5g/ day (albuminuria 1700 mg/day), and preserved renal function (CrS 1.1/ Ur 65 mg/dL, creatinine clearance 94 mL/min). The diagnosis of IgG/kappa monoclonal gammopathy was established based on serum and urine immunofixation results: M protein of 0.4 g/dL, serum kappa light chain level was 11.8 mg/L, and serum lambda light chain level was 1.16 mg/L, with a corresponding ratio of 10.15. Hemoglobin was 12.4 g/dL and calcium 9.0 mg/dL. Serum levels of immunoglobulin A (IgA), IgG, and IgM were decreased (596, 68, and 21 mg/dL, respectively). His C3 level was low at 74 mg/dL (normal range: 90-180 mg7dL), and his C4 level was normal (15 mg/dL). An expanded panel of complement testing was not performed. No other changes in the immune study were detected (negative antibodies anti-GBM, ANAs, anti-dsDNA, ANCAs, and cryoglobulins) and the viral serologies for hepatitis B, hepatitis C, and HIV were negative. The bone marrow aspirate showed 3.6% of plasma cells, 95% of these with an abnormal phenotype.

Renal biopsy showed mesangiocapillary proliferation with a membranoproliferative pattern on light microscopy, with endocapillary hypercellularity, lobulation, and thickened glomerular basement membranes with double contours; tubular atrophy and interstitial fibrosis of 5 and 10%, respectively. Immunoflurescence (IF) revealed mesangial and capillary wall positivity for C3 (2+). C1q was vestigial, with negative staining for immunoglobulins (IgG, IgA, IgM) or light chains κ and λ. In electron microscopy, mesangial, mesangiocapillary, and subendothelial immune-type deposits were observed (Figure 1).

Figure 1
Kidney biopsy. (A and C) Optical microscopy (HE and Masson’s trichrome, respectively) showing a membranoproliferative pattern, with endocapillary hypercellularity, lobulation, and thickened glomerular basement membranes; (B) Immunofluorescence with C3 staining; (D) Electron microscopy – mesangial, mesangiocapillary, and subendothelial immune-type deposits.

A diagnosis of C3 glomerulonephritis associated with monoclonal gammopathy of renal significance was made, and the patient was started on clone directed therapy in June 2022. He received 7 months of therapy with iv cyclophosphamide 300 mg/m², bortezomib (1.3 mg/m² weekly), and dexamethasone (40 mg weekly).

Two months after starting chemotherapy, a decrease in the M protein to 0.2 mg/dL and a reduction of free light chain ratio kappa/ lambda to 2.2, along with an improvement of proteinuria to 1.6 g/24 hours were detected. At the end of the treatment, the patient achieved complete hematologic response, with disappearance of the monoclonal protein on serum electrophoresis, normalization of the serum kappa/lambda ratio, and no detection of monoclonal components on urinary electrophoresis/immunofixation. Proteinuria further improved to 0.33 g/24 hours, erythrocyturia disappeared, and creatinine remained stable at 1.0 mg/dL.

He received no maintenance therapy and remains stable with complete hematologic response, preserved renal function, and proteinuria below 400 mg/24h 12 months after stopping the treatment (Figure 2).

Figure 2
Hematologic and renal responses. *Cyclophosphamide, bortezomib and dexamethasone.

Discussion

MGRS is a complex and challenging condition characterized by kidney damage induced by the secretion of a nephrotoxic monoclonal immunoglobulin (mIg). The pattern of the renal lesion is mostly determined by the intrinsic structural and physicochemical characteristics of the monoclonal protein (intact monoclonal immunoglobulins or immunoglobulin light chains), rather than by the rate of production or clone features¹,². This case report highlights the association between MGRS and C3GN.

C3 glomerulopathies are a group of rare kidney diseases driven by dysregulation of the complement AP⁷. C3G is characterized histopathologically by the accumulation of the C3 component in renal tissue. This finding, in the absence or near absence of immunoglobulin deposits, is the single diagnostic criterion. Terminal pathway dysregulation might also occur, especially in C3GN⁷.

Dysregulation of the AP may result from acquired or genetic changes. In most patients, the disease is caused by acquired factors, namely autoantibodies that target regulatory proteins of the complement system. The most common are C3 nephritic factors, which stabilize C3 convertase, increasing its half-life, but other autoantibodies have been identified such as C5 nephritic factors (which target C3bBbC3b), C4 nephritic factors (towards C4b2a), factor H and factor B autoantibodies. Genetic causes are less frequent and include mutations that result either in loss of function in genes responsible for regulatory proteins or in gain of function in activator proteins⁷,¹⁰,¹¹.

More recently, an association between monoclonal gammopathy and C3G has been described⁴,⁷. The pathophysiology of mIg-C3G is still being investigated, but evidence suggests an association between mIg and inappropriate activation of the AP pathway: monoclonal light chains can act as autoantibodies against factor H, resulting in decreased factor H activity, and mIg itself could act as C3 nephritic factor⁷,¹⁰. However, the monoclonal immunoglobulin does not always show antibody activity against complement regulatory proteins and is thought to activate the alternative pathway through other mechanisms⁴,¹⁰,¹². Genetic abnormalities in complement genes are rarely identified in mIg-C3G⁴,⁷,¹².

The clinical presentation of C3 glomerulopathy ranges from asymptomatic hematuria and proteinuria of variable degrees including the nephrotic range to an acute presentation with nephritic syndrome, acute kidney injury, or rapidly progressive glomerulonephritis⁷. Serum C3 levels are low in most patients, while C4 levels are usually normal; elevated serum levels of sC5b-9 may be present⁴,⁷. Patients with mIg-C3G are typically older compared to C3G without monoclonal Ig and tend to have higher serum creatinine and proteinuria at presentation⁴.

Renal biopsy is mandatory to establish the diagnosis⁷. All patients with MGUS with suspected kidney involvement, i.e. suspected MGRS (for example, presenting with proteinuria, hematuria, and/ or unexplained kidney function impairment), should undergo a kidney biopsy since the renal diagnosis can dramatically change the therapeutic and prognostic landscape of the disease. For the same reason, kidney biopsy is also recommended in patients with MGUS and other known risk factors for chronic kidney disease who have an atypical clinical course¹. The present case exemplifies the significant impact of a timely diagnosis coupled with effective treatment on the renal prognosis and course of the disease.

On light microscopy, C3G usually shows a membranoproliferative pattern, but can also show mesangial or endocapillary proliferation. Exudative, crescentic, and sclerosing patterns can be observed. The two major subtypes of C3 glomerulopathy, DDD and C3GN, are distinguished by their ultrastructural appearance: ill-defined, moderately electron-dense mesangial, subepithelial, and subendothelial deposits are seen in C3 glomerulonephritis, whereas highly electron-dense ‘sausage-like’ intramembranous deposits and mesangial rounded nodular deposits are seen in dense deposit disease. Subepithelial humps can occur in both subtypes⁷,¹¹. The immunofluorescence microscopy, key for diagnosis, shows staining for C3 of at least twice the intensity of any other immunoreactant and is typically negative for Ig (either heavy or light chains)⁷,¹³.

C3GN is the most common form of C3 glomerulopathy with monoclonal gammopathy. Importantly, a minority of patients (5–10%) with monoclonal gammopathy and findings on standard immunofluorescence consistent with C3GN will actually have a membranoproliferative glomerulonephritis with masked monoclonal deposits. These patients require additional immunofluorescence studies to be performed on protease-digested, paraffin-embedded tissue for identification of the monoclonal immunoglobulin in the deposits¹. The limited availability of these auxiliary techniques in our country precluded their utilization in this case.

Moreover, renal biopsy provides valuable prognostic information⁷,¹⁴. The Columbia University C3G histologic index, validated in 2017, assesses disease activity and chronicity based on histological features, including mesangial hypercellularity, endocapillary proliferation, membranoproliferative morphology, cellular and fibrocellular crescents, fibrinoid necrosis and interstitial inflammation (on a scale of 0–3). The features graded for the chronicity score include glomerulosclerosis, tubular atrophy, interstitial fibrosis (each on a scale of 0–3), and arteriosclerosis (on a scale of 0–1). In the study of Bomback et al.¹⁴, the estimated glomerular filtration rate at diagnosis, percent tubular atrophy, and percent interstitial fibrosis were the strongest independent predictors of progression to loss of kidney function. In a more recent yet smaller study from Caravaca-Fontán et al.¹², the C3G histologic index was applied to 23 patients with C3G and monoclonal gammopathy, with higher chronicity scores being associated with worse kidney outcomes. Notably, higher chronicity scores at the time of kidney biopsy may be the expression of a delayed diagnosis in this older population with mIg-C3G¹². Thus, although challenging, an early diagnosis, before chronic lesions develop, stands as a crucial prognostic factor, enabling therapeutic interventions to be effective at the renal parenchyma level.

Many older patients, especially aged ≥50 years who present with C3 glomerulopathy, will have a monoclonal gammopathy, indicative of MGRS⁴,¹²,¹⁵. In a large cohort from Mayo Clinic, monoclonal gammopathy was identified in only 8 of 52 (15%) patients <50 years of age, compared with 28 of 43 (65%) patients >50 years of age¹⁵. Thus, all patients aged ≥50 years with C3G should be screened for paraproteins by serum protein electrophoresis immunofixation and serum free light chain evaluation. A diagnosis of monoclonal gammopathy mandates further evaluation with a bone marrow biopsy to identify the clonal population responsible for mIg production¹,⁷. The most common underlying hematologic disease in patients with mIg-G3C is MGUS/MGRS, and IgG/κ is the most common mIg isotype²,⁴.

Expert opinion suggests that patients with C3 glomerulopathy should undergo a comprehensive complement evaluation, including overall complement activity assessment, measurements of serum levels of complement proteins and their split products, and screening for autoantibodies⁷. Genetic testing should also be considered, although its precise value in the clinical setting of patients with mIg-C3G remains to be determined⁷,¹². This is a limitation of our study, as neither autoantibody screening nor complement genetic studies were conducted. Nonetheless, the lack of this information doesn’t appear to have significantly affected the diagnostic and prognostic evaluation of our patient, as evidenced by his excellent response to treatment.

The best treatment for C3GN associated with MGRS has not been established⁷. However, there is increasing evidence suggesting a superiority of clone-targeted therapies in terms of kidney survival as compared with conventional immunosuppression or conservative management, highlighting the correlation between the reduction of mIg and better renal outcomes⁴,⁹,¹². Chauvet et al.⁸ found that patients who received chemotherapy, including bortezomib, reached better renal response than those receiving conservative/immunosuppressive therapy. In this study, achievement of a hematological response was significantly associated with higher kidney survival⁸. These results were latter reproduced by some observational studies, confirming the therapeutic superiority of clone-targeted therapies in terms of kidney survival and the correlation of hematologic response with improvement in proteinuria and renal outcomes⁴,⁹,¹²,¹³. Based on these findings, anti-myeloma agents like bortezomib, lenalidomide, or even daratumumab, should be considered as first-line therapy for C3G-MIg until further data are available. In normal clinical practice, it is sometimes difficult to encourage hematologists to perform this type of treatment in the absence of a neoplastic process or clear evidence of mIg deposition in kidney tissue, which is a challenge in the management of these patients. The potential role of newer complement-targeted therapies as adjunctive treatment in selected patients with mIg-C3G is yet to be assessed⁷.

Similarly, the optimal treatment for C3G without mIg has not been established. Most of these patients are treated with conventional immunosuppression (corticosteroids alone or corticosteroids plus other drugs), with mixed results⁷. In a study from Ravindran et al.⁴, there was no significant difference in renal survival among patients with mIg-C3G and patients with C3G without mIg. In the specific setting of mIg-C3G, clone-directed therapy may result in improved renal survival⁴,⁷,⁹,¹³.

The limited data on mIg-C3G in kidney transplant point to a high risk of disease recurrence in allograft recipients⁷. Besides, transplant recipients with C3G-mIg seem to have poor kidney outcomes despite the achievement of a hematological response in a few cases¹². In younger, selected patients who are transplant candidates, autologous stem cell transplant could be considered as a complementary therapy, helping to achieve a deeper and sustained or even a complete hematological response, which is essential to reduce the risk of recurrence, particularly after renal transplant¹⁶.

The treatment approach adopted in this case was clone-directed therapy. Remarkably, the patient achieved a complete hematologic response with disappearance of M-spike on serum electrophoresis and normalization of the serum free light chain kappa/lambda ratio. The success of the clone-directed therapy in this case highlights the importance of tailored treatment strategies in MGRS-associated C3G, in agreement with the most recent evidence⁴,⁸,⁹,¹²,¹³. Furthermore, an early diagnosis was established, with few signs of chronicity on renal biopsy. This, coupled with the efficacy of the clone-direct therapy, markedly influenced the patient’s renal prognosis. The long-term follow-up revealed sustained remission of the hematologic condition and proteinuria while maintaining preserved renal function, reinforcing that achieving a complete or deep hematologic response results in improved kidney outcomes.

Conclusions

In conclusion, this case underscores the intricate relationship between MGRS and C3GN, highlighting the importance of tailored treatment strategies. The patient exhibited an exceptional response to treatment, demonstrating the importance of early diagnosis and effective clone-directed therapy in improving renal prognosis. The long-term remission observed in both hematologic and renal parameters emphasizes the importance of clone-directed therapy and the need for vigilant follow-up in managing MGRS-associated C3G cases.

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Publication Dates

• Publication in this collection
  16 Sept 2024
• Date of issue
  Oct-Dec 2024

History

• Received
  24 May 2024
• Accepted
  26 July 2024