Monoclonal gammopathy of renal significance

# Overview
Monoclonal gammopathy of renal significance (MGRS) is a group of kidney disorders that are characterized an abnormal secretion of a monoclonal protein (M protein) from plasma cell clones or other B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma (MM) or any other B-cell malignancies. MGRS is considered a type of monoclonal gammopathy of undetermined significance (MGUS), as kidney is one of the most commonly targeted organs in MGUS. The lesions in MGRS fall under three main categories; lesions with organized deposits, lesions with non-organized deposits, and Lesions without immune deposits. MGRS must be differentiated from other diseases that cause monoclonal gammopathy such as Multiple myeloma, Chronic lymphocytic leukemia (CLL), and Lymphoplasmacytic lymphoma. Renal biopsy is the mainstay in the evaluation of MGRS. Following suspicion of MGRS, lab evaluation of kidney function should be performed by renal function testing, urinanalysis, and a complete metabolic panel. The main and most effective therapeutic modality is clone-directed therapy, based on the nature of the clone that releases the nephrotoxic monoclonal immunoglobulins; B-cell or plasma cell. In case of end-stage kidney disease, kidney transplantation is the best option.

# Historical Perspective
There is limited information about the historical perspective of MGUS or MGRS.

# Classification
There is no established system for the classification of monoclonal gammopathy.

# Pathophysiology
It is thought that MGRS is the result of monoclonal antibodies causing renal damage through multiple mechanisms:
- Mostly it is due to misfolding of a fragment of monoclonal immunoglobulin light chain, wiith subsequent formation of toxic amyloid multimers and fibrils (AL amyloidosis).
- Mutations in the variable domain, making it resistant to proteolysis; thus, prevent the recycling of free light chains in the endolysosomes in proximal tubular cells with crystallization and formation of intracytoplasmic crystals which cause lysosomal and cellular dysfunction ad failure of reabsorptive process (light chain proximal tubulopathy).
- In monoclonal immunoglobulin deposition disease (MIDD), monoclonal immunoglobulins show unique physicochemical features of the variable domain, such as abnormal glycosylation, positive charge, and hydrophobic residues. These characteristics result in their aggregation and deposition in the mesangium.
- Also in MIDD when a deletion mutation of the first constant domain of the heavy chain renders the heavy chain unable to bind the light chain to make a complete immunoglobulin.
- Exposure of monoclonal immunoglobulins (cryoglobulins) to temperatures below body temperature, it results in precipitation into microtubules or crystals with subsequent endothelial injury, thrombosis, and inflammation of glomerular arterioles and capillaries disrupting the integrity of the filtration barrier (crystalglobulinemia).
- Deposition of intact immunoglobulins in glomeruli causes complement activation.
- Deposition of noncryoglobulin microtubular is the hallmark of immunotactoid glomerulonephritis.
- Immunoglobulins deposition causes activation of the classical complement pathway, resulting in glomerular inflammation and endocapillary proliferation.
- Monoclonal immunoglobulins may cause direct activation of the alternative complement pathway, or dysregulation of the alternative complement pathway through autoantibody activity against factor H or other regulators of the alternative pathway. Deposition of C3 and complement terminal pathway proteins (C3 glomerulopathy).

## Characteristics of the Most Common Lesions in Monoclonal Gammopathy of Renal Significance (MGRS)
The lesions in MGRS fall under three main categories; lesions with organized deposits, lesions with non-organized deposits, and Lesions without immune deposits.

### Lesions with Organized Deposits:
- Immunoglobulin-related Amyloidosis (AL, 94%; AH and AHL, 6%)
Renal lesions: heavy proteinuria (median protein, 56 g/day), nephrotic syndrome (66%), mild chronic kidney disease (CKD) (median creatinine,1.2 mg/dl); hematuria and hypertension is uncommon
Pathologic findings: light microscopy shows congo redpositive deposits, mostly in glomeruli and vessels, smudgy deposits on immunofluorescence positive for 1 LC in AL (mostly ), 1 HC (mostly 1 or 4) with CH1 domain deletion in AH, 1 HC and 1 LC in AHL, and electron microscopy shows randomly oriented fibrils (714 nm)
Extrarenal manifestations: heart failure, postural hypotension, peripheral neuropathy, GI symptoms, carpal tunnel syndrome, liver involvement
Hematologic disease: MGRS (80%), multiple myeloma (16%)  and other lymphomas 
Identification of M Protein: SPEP-SIF: 6688%, UPEP-UIF: 6780%, and abnormal SFLC: 7888%
- Renal lesions: heavy proteinuria (median protein, 56 g/day), nephrotic syndrome (66%), mild chronic kidney disease (CKD) (median creatinine,1.2 mg/dl); hematuria and hypertension is uncommon
- Pathologic findings: light microscopy shows congo redpositive deposits, mostly in glomeruli and vessels, smudgy deposits on immunofluorescence positive for 1 LC in AL (mostly ), 1 HC (mostly 1 or 4) with CH1 domain deletion in AH, 1 HC and 1 LC in AHL, and electron microscopy shows randomly oriented fibrils (714 nm)
- Extrarenal manifestations: heart failure, postural hypotension, peripheral neuropathy, GI symptoms, carpal tunnel syndrome, liver involvement
- Hematologic disease: MGRS (80%), multiple myeloma (16%)  and other lymphomas 
- Identification of M Protein: SPEP-SIF: 6688%, UPEP-UIF: 6780%, and abnormal SFLC: 7888%
- Monoclonal Immunotactoid Glomerulonephritis
Renal lesions: heavy proteinuria (median protein, 6 g/day), nephrotic syndrome (5970%), CKD (median creatinine,1.5 mg/dl), hematuria (7489%), hypertension (5684%), hypocomplementemia (33%)
Pathologic findings: light microscopy shows atypical membranous, membranoproliferative, mesangial, or endocapillary proliferative glmomerulonephritis (GN) , immunofluorescence shows monotypic IgG (mostly IgG1) granular deposits in mesangium and glomerular basement membrane (GBM), electron microscopy shows glomerular microtubular deposits (1460 nm) with frequent parallel arrangement
Extrarenal manifestations are rare such as mononeuritis multiplex and dermal capillaritis
Hematologic disease: CLL (3745%), MGRS (52%), other small cell lymphomas (811%), MM(4%)
Identification of M Protein: SPEP-SIF: 50%, UPEP-UIF: 42%, and abnormal SFLC: 1928%
- Renal lesions: heavy proteinuria (median protein, 6 g/day), nephrotic syndrome (5970%), CKD (median creatinine,1.5 mg/dl), hematuria (7489%), hypertension (5684%), hypocomplementemia (33%)
- Pathologic findings: light microscopy shows atypical membranous, membranoproliferative, mesangial, or endocapillary proliferative glmomerulonephritis (GN) , immunofluorescence shows monotypic IgG (mostly IgG1) granular deposits in mesangium and glomerular basement membrane (GBM), electron microscopy shows glomerular microtubular deposits (1460 nm) with frequent parallel arrangement
- Extrarenal manifestations are rare such as mononeuritis multiplex and dermal capillaritis
- Hematologic disease: CLL (3745%), MGRS (52%), other small cell lymphomas (811%), MM(4%)
- Identification of M Protein: SPEP-SIF: 50%, UPEP-UIF: 42%, and abnormal SFLC: 1928%
- Type 1 Cryoglobulinemic Glomerulonephritis
Renal lesions: proteinuria, nephrotic syndrome (38%), CKD (mean creatinine, 3 mg/dl), hematuria (71%), hypertension, hypocomplementemia (mostly low C4) (58%)
Pathologic findings: light microscopy shows membranoproliferative or endocapillary proliferative GN with monocyte infiltration and often immune thrombi, immunofluorescence: shows monotypic Ig (mostly IgG or IgM) granular deposits in glomeruli and vessels, and electron microscopy shows microtubular extracellular electron-dense deposits and occasional intracellular crystals
Extrarenal manifestations: purpuric rash, skin ulcers, peripheral neuropathy, and arthralgias
Hematologic disease: MGRS (50%), B-cell lymphoma (2456%), MM (7%)
Identification of M Protein: SPEP-SIF: 76%
- Renal lesions: proteinuria, nephrotic syndrome (38%), CKD (mean creatinine, 3 mg/dl), hematuria (71%), hypertension, hypocomplementemia (mostly low C4) (58%)
- Pathologic findings: light microscopy shows membranoproliferative or endocapillary proliferative GN with monocyte infiltration and often immune thrombi, immunofluorescence: shows monotypic Ig (mostly IgG or IgM) granular deposits in glomeruli and vessels, and electron microscopy shows microtubular extracellular electron-dense deposits and occasional intracellular crystals
- Extrarenal manifestations: purpuric rash, skin ulcers, peripheral neuropathy, and arthralgias
- Hematologic disease: MGRS (50%), B-cell lymphoma (2456%), MM (7%)
- Identification of M Protein: SPEP-SIF: 76%
- Light-chain Proximal Tubulopathy
Renal lesions: proteinuria (median protein, 1.52.5 g/day), mild CKD (median creatinine, 1.92.0 mg/dl), proximal tubulopathy with or without complete Fanconi syndrome
Pathologic findings: light microscopy shows proximal tubular swelling, immunofluorescence shows proximal tubular staining  (of crystalline variant) or  (mostly of noncrystalline variant), electron microscopy shows proximal tubular crystals or lysosomal inclusions
Extrarenal manifestations: stress fracture (40%)
Hematologic disease: MGRS (6180%), MM (1233%), and others (38%)
Identification of M Protein: SPEP-SIF: 71100%, UPEP-UIF: 94100%, and abnormal SFLC: 91100%
- Renal lesions: proteinuria (median protein, 1.52.5 g/day), mild CKD (median creatinine, 1.92.0 mg/dl), proximal tubulopathy with or without complete Fanconi syndrome
- Pathologic findings: light microscopy shows proximal tubular swelling, immunofluorescence shows proximal tubular staining  (of crystalline variant) or  (mostly of noncrystalline variant), electron microscopy shows proximal tubular crystals or lysosomal inclusions
- Extrarenal manifestations: stress fracture (40%)
- Hematologic disease: MGRS (6180%), MM (1233%), and others (38%)
- Identification of M Protein: SPEP-SIF: 71100%, UPEP-UIF: 94100%, and abnormal SFLC: 91100%

### Lesions with Non-organized Deposits
- Monoclonal Immunoglobulin Deposition Disease (MIDD)
Renal lesions: proteinuria (median protein, 1.82.4 g/day), nephrotic syndrome (22%), CKD (median creatinine, 3 mg/dl), hematuria (5862%), and hypertension (5583%)
Pathologic findings: light microscopy shows nodular glomerulosclerosis (67% of cases), thickened tubular basement membrane (TBM), immunofluorescence shows linear deposits along glomerular basement membrane (GBM), TBM, and vessels, and electron microscopy shows punctate electron-dense deposits along GBM, TBM, and vessels
Extrarenal manifestations: mostly hepatic and cardiac manifestations (35%)
Hematologic disease: MGRS (6478%), MM (1834%), and others (lymphoma) (2%)
Identification of M Protein: SPEP-SIF: 64%, UPEP-UIF: 68%, and abnormal SFLC: 99100%
- Renal lesions: proteinuria (median protein, 1.82.4 g/day), nephrotic syndrome (22%), CKD (median creatinine, 3 mg/dl), hematuria (5862%), and hypertension (5583%)
- Pathologic findings: light microscopy shows nodular glomerulosclerosis (67% of cases), thickened tubular basement membrane (TBM), immunofluorescence shows linear deposits along glomerular basement membrane (GBM), TBM, and vessels, and electron microscopy shows punctate electron-dense deposits along GBM, TBM, and vessels
- Extrarenal manifestations: mostly hepatic and cardiac manifestations (35%)
- Hematologic disease: MGRS (6478%), MM (1834%), and others (lymphoma) (2%)
- Identification of M Protein: SPEP-SIF: 64%, UPEP-UIF: 68%, and abnormal SFLC: 99100%
- Proliferative Glomerulonephritis with Monoclonal IgG Deposits (PGNMID)
Renal lesions: heavy proteinuria (mean protein, 6 g/day), nephrotic syndrome (49%), CKD (mean creatinine, 2.8 mg/dl), hematuria (77%), and hypertension (38%)
Pathologic findings: light microscopy shows membranoproliferative, endocapillary proliferative, or membranous GN, immunofluorescence shows monotypic Ig (mostly IgG3) granular deposits in mesangium and GBM, and electron microscopy shows electron-dense deposits in glomeruli
No extrarenal manifestations
Hematologic disease: MGRS (96%), MM (34%), lymphoma (1%)
Identification of M Protein: SPEP-SIF: 2030%, UPEP-UIF: 11%,and abnormal SFLC: 21%
- Renal lesions: heavy proteinuria (mean protein, 6 g/day), nephrotic syndrome (49%), CKD (mean creatinine, 2.8 mg/dl), hematuria (77%), and hypertension (38%)
- Pathologic findings: light microscopy shows membranoproliferative, endocapillary proliferative, or membranous GN, immunofluorescence shows monotypic Ig (mostly IgG3) granular deposits in mesangium and GBM, and electron microscopy shows electron-dense deposits in glomeruli
- No extrarenal manifestations
- Hematologic disease: MGRS (96%), MM (34%), lymphoma (1%)
- Identification of M Protein: SPEP-SIF: 2030%, UPEP-UIF: 11%,and abnormal SFLC: 21%
- C3 Glomerulopathy with Monoclonal Gammopathy
Renal lesions: proteinuria (median protein, 3.2 g/day), nephrotic syndrome (43%), CKD (median creatinine,1.8 mg/dl), hematuria (8489%),low C3 (3443%)
Pathologic findings: light microscopy shows membranoproliferative, mesangioproliferative, or endocapillary proliferative GN, immunofluorescence: C3 granular deposits in mesangium and GBM (with paucity of Ig deposits), electron microscopy shows ill-defined electron-dense deposits in C3GN and intramembranous and mesangial highly electron-dense deposits in dense-deposit disease
No extrarenal manifestations
Hematologic disease: MGRS (8290%), MM (414%), lymphoma (6%)
Identification of M Protein: SPEP-SIF: 99100% UPEP-UIF: 100%, and abnormal SFLC: 5375%
- Renal lesions: proteinuria (median protein, 3.2 g/day), nephrotic syndrome (43%), CKD (median creatinine,1.8 mg/dl), hematuria (8489%),low C3 (3443%)
- Pathologic findings: light microscopy shows membranoproliferative, mesangioproliferative, or endocapillary proliferative GN, immunofluorescence: C3 granular deposits in mesangium and GBM (with paucity of Ig deposits), electron microscopy shows ill-defined electron-dense deposits in C3GN and intramembranous and mesangial highly electron-dense deposits in dense-deposit disease
- No extrarenal manifestations
- Hematologic disease: MGRS (8290%), MM (414%), lymphoma (6%)
- Identification of M Protein: SPEP-SIF: 99100% UPEP-UIF: 100%, and abnormal SFLC: 5375%

### Lesions without immune deposits
- Thrombotic Microangiopathy with Monoclonal Gammopathy
Renal lesions: proteinuria (median protein, 3.2 g/day), nephrotic syndrome (43%), CKD (median creatinine 1.8 mg/dl), hematuria (8489%), hypocomplementemia (50%)
Pathologic findings: light and electron microscopy show GBM duplication, mesangiolysis, subendothelial fluff, thrombosis and  immunofluorescence reveals no Ig deposits
Extrarenal manifestations: microangiopathic hemolytic anemia, POEMS syndrome
Hematologic disease: MGRS (90%), MM (5%), lymphoma (5%)
Identification of M Protein: SPEP-SIF: 95%, UPEP-UIF: 33%, and abnormal SFLC: 28%
- Renal lesions: proteinuria (median protein, 3.2 g/day), nephrotic syndrome (43%), CKD (median creatinine 1.8 mg/dl), hematuria (8489%), hypocomplementemia (50%)
- Pathologic findings: light and electron microscopy show GBM duplication, mesangiolysis, subendothelial fluff, thrombosis and  immunofluorescence reveals no Ig deposits
- Extrarenal manifestations: microangiopathic hemolytic anemia, POEMS syndrome
- Hematologic disease: MGRS (90%), MM (5%), lymphoma (5%)
- Identification of M Protein: SPEP-SIF: 95%, UPEP-UIF: 33%, and abnormal SFLC: 28%
Abbreviations
AH: heavy-chain amyloidosis
AHL: heavy- and light-chain amyloidosis
AL: light-chain amyloidosis
GI: gastrointestinal
HC: heavy chain
HCDD: heavy-chain deposition disease
Ig: immunogobulin
LC: light chain
LCDD: light-chain deposition disease
LHCDD: light- and heavy-chain deposition disease
LPL: lymphoplasmacytic lymphoma
POEMS: polyneuropathy, organomegaly, endocrinopathy, M component, and skin changes
SFLC: serum free light-chain
SPEP-SIF: serum protein electrophoresis with immunofixation
UPEPUIF: urine protein electrophoresis with immunofixation

# Causes
The cause of MGUS or MGRS has not been identified.

# Differentiating MGUS from other Diseases
MGRS must be differentiated from other diseases that cause monoclonal gammopathy, such as:
- Multiple myeloma: it is characterized by more than 10% the bone marrow infiltrated with plasma cells or a monoclonal spike of more than 3 gm. per dl, in addition to end-organ damage as determined by the CRAB criteria (hypercalcemia, renal insufficiency, anemia, and bone lesions).
- Chronic lymphocytic leukemia (CLL)
- Lymphoplasmacytic lymphoma (previously called Waldenstrom macroglobulinemia)
- Smoldering multiple myeloma or smoldering lymphoplasmacytic lymphoma: these are characterized by fulfilling the tumor burden with no evidence of end-organ damage
- Chronic hepatitis C infection
- Connective tissue diseases

# Epidemiology and Demographics
- Kidney disease is a major common cause of morbidity and mortality affecting 37 million people in the United States.
- Apart from hypertension and diabetes mellitus, monoclonal gammopathy has been found to be a major cause of kidney damage in the form of glomerular, tubulointerstitial, and vascular renal lesions.
- The prevalence of MGRS is unknown.
- Olmsted County, Minnesota reported that the incidence of MGUS 7 to 59 times as high as the incidence of glomerular diseases. Also, the incidence was higher in males above 50 years of age.
- There is no racial predilection to MGUS.

# Risk Factors
Common risk factors in the development of MGUS or MGRS include old age, male gender, African American race, and positive family history.

# Screening
There is no evidence to recommend routine screening for MGUS or MGRS.

# Natural History, Complications, and Prognosis
If left untreated, approximately 1% of patients with MGUS may progress to develop multiple myeloma, AL amyloidosis, and lymphoma.

# Diagnosis

## Diagnostic Study of Choice
Renal biopsy is the mainstay in the evaluation of MGRS. Following suspicion of MGRS, lab evaluation of kidney function should be performed by renal function testing, urinanalysis, and complete metabolic panel.
- Biopsy is recommended in the following conditions:
Acute kidney injury (AKI) grade 3
eGFR less than 80 ml/min. and more than 2 ml per year decline
Proteinuria more than 1 gm./24 hr.
Albumin/creatinine ratio more than 30 mg./mmol
Fanconi syndrome
- Acute kidney injury (AKI) grade 3
- eGFR less than 80 ml/min. and more than 2 ml per year decline
- Proteinuria more than 1 gm./24 hr.
- Albumin/creatinine ratio more than 30 mg./mmol
- Fanconi syndrome
- Biopsy is not recommended if:
Stable eGFR
Normal urinanalysis
No evidence of light chain proteinuria
- Stable eGFR
- Normal urinanalysis
- No evidence of light chain proteinuria
- After confirming the diagnosis of MGRS-related disease, a hematologic evaluation should be done to determine the clone that is secreting the monoclonal immunoglobulins.
- A bone marrow biopsy is important for clonal identification.
- Lymph node biopsy or  flow cytometry can help to identify the clone, especially in patients with lymphoma and CLL.
- Computed tomography (CT) or positron emission tomography (PET) scan may help to identify those lesions outside the bone marrow, such as lymph nodes.
- Apart from clonal identification, testing of genetic markers such as BCL2 gene or  t(11;14) in bone marrow biopsy specimens may be of value for providing additional treatment options for selected patients.

## History and Symptoms
The majority of patients with MGUS or MGRS are asymptomatic.

## Physical Examination
Common physical examination findings of MGUS or MGRS include the physical findings of the associated disorders such as heart failure, liver damage, arthralgia, stress fracture, peripheral neuropathy, or skin ulcers

## Laboratory Findings
Laboratory findings consistent with the diagnosis of MGUS or MGRS include elevated monoclonal proteins but less than 3gm/dl, proteinuria or hematuria on urinanalysis, pathologic findings of various types of glomerulonephritis, and plasma cells expansion but still less than 10% on bone marrow examination.

## Electrocardiogram
There are no ECG findings associated with MGUS.

## X-ray
There are no specific X-ray findings associated with MGUS or MGRS.

## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with MGUS or MGRS. However, an echocardiography may show an evidence of the complications, such as heart failure.

## CT scan
There are no CT scan findings associated with MGUS or MGRS. In some cases, a CT scan may be helpful in the diagnosis of complications of MGUS/MGRS, which include stress fracture and bone abnormalities.

## MRI
There are no MRI findings associated with MGUS or MGRS, but an MRI can be used for diagnosis of complications of MGUS/MGRS, such as stress fracture and bone abnormalities.

## Other Imaging Findings
There are no other imaging findings associated with MGUS or MGRS.

## Other Diagnostic Studies
There are no other diagnostic studies associated with MGUS or MGRS.

# Treatment

## Medical Therapy
- The mainstay of treatment has to be based on the nature of the clone that releases the nephrotoxic monoclonal immunoglobulins; B-cell or plasma cell.
- The main and most effective therapeutic modality is clone-directed therapy which is better than the immunosuppressive therapy.
- The priority in the management of MGRS is preservation of kidney function.
- In case of advanced CKD, the objective of of clone-directed therapy should be redirected to reducing the risk of recurrence after kidney transplantation.
- If the patient is not a candidate for transplantation, treatment should be given only in case of extrarenal involvement abd fulfilling the diagnostic criteria of a malignant process.
- A very good partial and minimum hematologic response that is sufficient for preservation of the renal function is characterized by a difference between involved and uninvolved free light chain of less than 4 mg per dl or  more than 90% decline of the involved free light chain. The most effective agents for achieving this purpose are mentioned in the table below.
- Monitoring of the hematologic measures (serum free light-chain level and the monoclonal spike) and renal function testing (serum creatinine and urinary protein levels) is necessary  to evaluate the response to treatment regimen and avoid the undesirable adverse effects.

## Surgery
- The mainstay of treatment for MGRS is medical therapy. Surgery (kidney transplantation) is usually reserved for patients with end-stage kidney disease.
- Eradication of monoclonal immunoglobulins or at least reaching a very good partial response are necessary before kidney transplantation to avoid the recurrence and the subsequent graft loss.

# Primary Prevention
There are no established measures for the primary prevention of MGUS/MGRS.

# Secondary Prevention
There are no established measures for the secondary prevention of MGUS/MGRS.