Paraprotein-related kidney disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ali Poyan Mehr, M.D. [2]

Synonyms and keywords: monoclonal gammopathy of renal significance; MGRS; paraproteinemia

Overview

Paraproteinemia refers to the presence of abnormal protein or protein fragments in the blood. The proteins referred to are immunoglobulins (or fragments of), and are of monoclonal origin (M-spike). Under certain circumstances these circulating monoclonal immunoglobulins are deposited in the renal tissues and can lead to various forms of renal disease.

Historical Perspective

In 1848, Henry Bence Jones (http://rstl.royalsocietypublishing.org/content/138/55) reported on the discovery of an "new substance" in the urine of an ill patient. Over the course of the history, this protein was termed "Bence Jones" and found to be associated with "myeloma". The term "myeloma kidney" was used first by Alfred von Decastello in 1909.

By 1939 the abnormal band described in serum electrophoresis of myeloma patients as "M-spike", was found to be due to immuneglobulin proteins.

Subsequent studies were able to further characterize these abnormal immunoglobulins and define as monoclonal kappa or lambda light chains, and confirm Bence Jones proteins to be the same as the circulating monoclonal immuneglobulins (para-proteins). (http://medcraveonline.com/UNOAJ/UNOAJ-03-00078.pdf)

Classification

• Paraprotein-related kidney disease may be classified according to the type of renal involvement and the underlying hematologic disorder into at least 10 various subtypes:

• AL Amyloidosis (either due to lambda or kappa light chains (AL), or due to heavy chains (AH), or both (ALH))
• Cryoglobulinemic GN, Waldenstrom type
• Cryoglobulinemic GN, Multiple Myeloma
• Cryglobulinemia type I or II: Ideopathic, lymphoma
• Immunotactoid Glomerulopathy
• Fibrillary Glomerulopathy
• Light chain deposition disease
• Heavy chain deposition disease
• Mixed light and heavy chain deposition disease
• Proliferative GN with monoclonal Ig
• Cast nephropathy

Pathophysiology

Here, the pathophysiology of paraprotein-related kidney disease will be discussed. For the pathophysiology of clonal plasma cell or B-cell disorders, including multiple myeloma, please refer to the corresponding chapters.

Monoclonal gammopathies (abnormal amounts of immunoglobulins from a single B-cell clone) can reflect a disease process, but also be benign (PMID:10926917).

The most widely recognized renal disorders due to paraproteinemias is light chain cast nephropathy (PMID:25607108 )..

depending on the burden of the underlying plasma cell or B-cell clone. In the first group of renal disorders, large amounts of all or part of the MIg is secreted and is associated with a high tumor mass B-cell proliferation. This condition characterizes: 1- light-chain cast nephropathy, the most common cause of acute kidney injury in multiple myeloma (MM) and 2-thrombi in high tumor mass Waldenstrom’s macroglobulinemia. The second group of MIg-related renal lesions are mainly seen in patients with a small B-cell clone and low malignant potential. They may also occur during symptomatic B-cell proliferations (PMID:25607108 ).

Many of these nonmalignant clones are classified as: 1- monoclonal gammopathy of undetermined significance (MGUS- with <3 g/dl of monoclonal protein and <10% bone marrow plasma cells) or 2- smoldering MM (with >3 g/dl of monoclonal protein and/or >10% bone marrow plasma cells) and they do not produce any end organ damage.

While Monoclonal gammopathy of renal significance (MGRS) and Symptomatic MM are defined by evidence  of  end  organ  damage.

Clinical and biological surveillance is the only required treatment of MGUS, smoldering MM and low-grade lymphomas,  because they  may  remain  asymptomatic  over  a prolonged period of time and studies have shown chemotherapy not to  be  beneficial  in  the  majority  of  patients.

MGRS is consistent with MGUS hematologic-wise but because of severe consequences produced in the kidneys (and sometimes in other organs), early detection and suppression of MIg secretion by chemotherapy is crucial in MGRS.

MGRS related kidney disorders include AL amyloidosis, proliferative glomerulonephritis with MIg deposits (PGNMID), C3 glomerulopathy with monoclonal gammopathy, light-chain deposition disease (LCDD) and immunotactoid glomerulopathy. Kidney biopsy is indicated in most cases. Other diagnostic ways include light microscopy, immunofluorescence (IF), electron microscopy, and in some cases IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Besides, complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required (PMID:25607108).

• MGRS could also be caused by mechanisms other than deposition of MIg, which could be responsible for another spectrum of MGRS related kidney disorders (PMID:25607108).

The type of kidney involvement highly depends on the specific characteristics of the paraprotein.

• AL Amyloidosis (either due to lambda or kappa light chains)

AL amyloidosis is caused by the deposition of amyloid deposits in extracellular spaces. These amyloid proteins are formed by light chains (hence AL for amyloid light chain) .These deposits may infiltrate the glomerular basement membrane or may be localized on both of its sides. Glomerular amyloid deposition produces a nonproliferative, noninflammatory glomerulopathy and enlargement of the kidney, often with heavy proteinuria. Immunoglobulin-Associated amyloidosis (AL amyloidosis) is the most frequent and severe form amyloidosis affecting the kidneys.

• Cryoglobulinemic GN, Waldenstrom type

• Cryoglobulinemic GN, Multiple Myeloma

• Cryglobulinemia type I: Ideopathic

• Immunotactoid Glomerulopathy

• Fibrillary Glomerulopathy

• Monoclonal immunoglobulin deposition disease, including light chain deposition disease and heavy chain deposition disease:

Monoclonal immunoglobulin deposition disease(MIDD) includes light chain deposition disease (LCDD) as the most common pattern, heavy chain deposition disease (HCDD) and light and heavy chain deposition disease (LCDD/HCDD). MIDD is caused by the overproduction and extracellular deposition of a monoclonal immunoglobulin protein. These deposits in LCDD are composed of kappa rather than lambda light chains in approximately 80% of cases.

• Proliferative GN with monoclonal Ig

• Cast nephropathy

Causes

Para-protein-related kidney disease can be caused by all many forms of plasma cell neoplasms ad B-cell lympho-proliferative disorders. These include:

Plasma cell neoplasms:

Smoldering myeloma (defined as: ____)

Multiple Myeloma (defined as___)

Plasmocytoma

B-Cell lymphoma

AL Amyloidosis:

AL Amyloidosis is is caused by the deposition of Amyloid deposits in extracellular spaces which could affect various organs.  Albeit,  the precursor proteins are different but they all have unique Congo red staining characteristics which is because of the same antiparallel beta pleated sheet configuration on X-ray diffraction.

All types of amyloid contain a 25Kdglycoprotein, serum amyloid P component (SAP) and C-reactive protein. Subsets of heparin and dermatan sulfated glycosaminoglycan (GAGS) and proteoglycans may be found in amyloid deposits. In AL amyloidosis, plasma cells produce variable portion of immunoglobulin light chains which are the source of amyloid fibrils.

• These deposits may infiltrate the glomerular basement membrane (GMB) or may be localized on both its sides. Advanced amyloid produces a nonproliferative, noninflammatory glomerulopathy and enlargement of the kidney. The most frequent and severe amyloidosis affecting the kidney is Immunoglobulin-Associated amyloidosis (AL amyloidosis). may be caused by either [cause1], [cause2], or [cause3].
• [Disease name] Fibrillary Glomerulopathy is caused by a mutation in the [gene1], [gene2], or [gene3] gene[s].
• Monoclonal immunoglobulin deposition disease(MIDD) includes light chain deposition disease (LCDD) as the most common pattern, heavy chain deposition disease (HCDD) and  light and heavy chain deposition disease (LCDD/HCDD). MIDD is caused  by the overproduction and extracellular deposition of a monoclonal immunoglobulin protein. These deposits in LCDD are composed of kappa rather than lambda light chains in approximately 80% of cases.

• There are no established causes f or [disease name].
• Cast nephropathy which is the most common form of kidney disease in patients with MM is occurred because of coprecipitation of immunoglobulin free light chains (FLCs) with Tamm-Horsfall glycoprotein (THP). this consequently causes the obstruction of the ascending limb of the loop of Henle, and the rapid decline in renal function (Treating myeloma cast nephropathy without treating myeloma).
• clonal proliferation of immunoglobulin-producing plasma cells is the cause of multiple

myeloma and monoclonal gammopathy of undetermined significance (MGUS). These neoplastic cells stop synthesizing the normal heavy chain component of the immunoglobulin molecule and start secreting only k or l light chains (Monoclonal Gammopathy-Associated Proliferative Glomerulonephritis).

monoclonal gammopathies of renal significance (MGRS), is kidney diseases due to monoclonal Ig (MIg) deposition but do not meet criteria for overt multiple myeloma (Bridging the Divide: An Onco-Nephrologic Approach to the Monoclonal Gammopathies of Renal Significance).

MGUS/smoldering MM and MGRS are distinguished not by the quantity of the plasma cell clone and its

secreted paraprotein, but by whether it results in end organ damage.

Differentiating [disease name] from other Diseases

• [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as:

• [Differential dx1]
• [Differential dx2]
• [Differential dx3]

Epidemiology and Demographics

• The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide.
• In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location].

Age

• Patients of all age groups may develop [disease name].

• [Disease name] is more commonly observed among patients aged [age range] years old.
• [Disease name] is more commonly observed among [elderly patients/young patients/children].

Gender

• [Disease name] affects men and women equally.

• [Gender 1] are more commonly affected with [disease name] than [gender 2].
• The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.

Race

• There is no racial predilection for [disease name].

• [Disease name] usually affects individuals of the [race 1] race.
• [Race 2] individuals are less likely to develop [disease name].

Risk Factors

• Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

Natural History, Complications and Prognosis

• The majority of patients with [disease name] remain asymptomatic for [duration/years].
• Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
• If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
• Prognosis is generally [excellent/good/poor], and the [1/5/10­year mortality/survival rate] of patients with [disease name] is approximately [#%].

Diagnosis

Diagnostic Criteria

• The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:

• [criterion 1]
• [criterion 2]
• [criterion 3]
• [criterion 4]

Symptoms

• Cryoglobulinemic GN, Waldenstrom type is presented by:fatigue,weight loss,bleeding, visual disturbances, peripheral neuropathy, hepatosplenomegaly, lymphadenopathy, anemia and hyperviscosity syndrome.

Renal involvement in Waldenstrom macroglobulinemia is uncommon but glomerular lesions are found in some patients. Which is manifested by microscopic hematuria and proteinuria, and renal failure.

Physical Examination

• Patients with [disease name] usually appear [general appearance].
• Physical examination may be remarkable for:

• [finding 1]
• [finding 2]
• [finding 3]
• [finding 4]
• [finding 5]
• [finding 6]

Laboratory Findings

For the work-up of monoclonal immunoglobulin depositions in the glomerulus one may consider the following:

• Serum and urine protein electrophoresis are good starter, but least sensitive test (Sensitivity of SPEP ~88% in patients with MM, ~66% in AL amyloidosis, ~56% in light chain deposition disease, and 15% in monoclonal gammopathy related GN)
• Serum and urine immunofixation may significantly increase the sensitivity of detecting monoclonal paraproteins.
• Additional serum free light chain assay (most sensitive test), and a skewed kappa/lambda ratio can further point toward an abnormal production of either of them (ration is also affected in CKD and infection!).
• Flow cytometry of bone marrow (+/- peripheral blood) may further help identify to source of the monoclonal Ig production. Be aware that neoplastic clones producing monoclonal Ig can be plasma cell clones (multiple myeloma), as well as B cell clones (B-cell lymphoma, CLL, Waldenstrom macroglobulinemia).

Imaging Findings

• There are no [imaging study] findings associated with [disease name].

• [Imaging study 1] is the imaging modality of choice for [disease name].
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

• Treatment options for monoclonal gammopathies of renal significance are borrowed from guidelines and protocols used for hematological malignancies, and based on anecdotal experiences and retrospective case reviews. This may include: Combination therapy for plasma cell depletion with bortezomib, cyclophosphamide, and dexamethasone for NON-IgM type monoclonal Ig deposits in glomerulus. Combination or single agent therapy for B-cell depletion with rituximab or cyclophosphamide in case of IgM type deposition.