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Written by: Sai Achi, MD
Infographics by: Corina Teodosiu, MD
Expert reviewer: Tiffany Caza, 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.
Described as early as 1844, little was known of multiple myeloma (MM) or paraproteinemias. Thomas Alexander McBean, a well-known tradesman, is perhaps the most well-known historical example of multiple myeloma where on autopsy, his body was described to have “soft, brittle, readily fractured ribs'' and a “gelatiniform substance of a blood-red colour and unctuous feel”. Prior to Mr. McBean’s demise, when corresponding with none other than Henry Bence Jones, McBean’s physician described a urine sample as “of very high specific gravity. When boiled, it becomes slightly opaque. On the addition of nitric acid, it effervesces, assumes a reddish hue, and becomes quite clear, but as it cools, assumes the consistency and appearance which you see. Heat liquefies it.” In fact, MM was once known as Kahler's disease, named after Professor Otto Kahler of Prague. The discovery of paraproteinemia would not occur until 1928 by Perlzweig et al. Paraproteinemia, also known as a monoclonal gammopathy, is a result of too many immunoglobulin proteins produced in the bone marrow, typically due to an immunoproliferative disorder or hematologic malignancy like multiple myeloma (MM) and sometimes lymphoma. Since then, our understanding of MM has expanded with new therapeutic interventions revolutionizing how we treat MM. However, with time and understanding, we have also learned that MM is one manifestation of the more general paraproteinemias. As it applies to nephrologists, the diagnosis becomes more nuanced when a paraproteinemia does not meet MM diagnostic criteria and falls into the category of either monoclonal gammopathy of unknown significance (MGUS) or monoclonal gammopathy of renal significance (MGRS). MGRS indicates that a monoclonal paraprotein is resulting in end-organ damage and is responsible for kidney dysfunction. Often, we find ourselves asking the question: does a patient with paraproteinemia simply have MGUS, or an MGRS? How can you tell the difference?
The following table highlights the monoclonal gammopathy classification:
Renal impairment is a defining characteristic of MM. Prior guidelines define renal dysfunction could be an elevation of serum creatinine or even include proteinuria without a significant increase in Cr and can be seen in cases such as early light chain deposition disease or amyloidosis. However, those guidelines did not explain the nature of renal dysfunction. When a paraproteinemia did not meet the diagnostic criteria of MM, but clearly had a monoclonal component, MGUS was introduced to better describe this entity. More recently, the term MGRS emerged, which represents a condition in which a paraproteinemia with renal involvement is observed, yet does not meet the diagnostic criteria for MM.
DIVERSITY OF DISEASE
The manner in which monoclonal immunoglobulins (Ig) can lead to kidney damage is dependent on the severity of tumor burden. One of the most well-known renal manifestations of high-burden of disease is light chain cast nephropathy, also known as myeloma kidney, resulting in acute kidney injury where light chains bind to Tamm-Horsfall proteins and form complexes of obstructive casts in nephron tubules. For this to occur, there must be high free light chain titers. Light chain cast nephropathy is not considered a MGRS, but a myeloma defining event. Yet very rarely, it can be seen in lymphoplasmacytic lymphoma or high-grade CLL (chronic lymphocytic leukemia).
The mechanisms by which MGRS can manifest are incredibly diverse. For example, amyloidosis occurs from the misfolding of the monoclonal Ig light chain fragments, thereby resulting in diffuse accumulation of amyloid multimers and fibrils. Light chain mutations in the variable domain can become resistant to free light chain recycling in the proximal tubule, resulting in a proximal tubulopathy. In monoclonal Ig deposition disease (MIDD), aggregation and deposition of the Ig in the mesangium and glomerular basement membrane (GBM) leads to phenotypic changes whereby the monoclonal heavy chains experience a deletion in their constant region, rendering them unable to bind to the light chain. Cryoglobulins, cold-sensitive Igs, precipitate in colder temperatures, forming structures that can occlude and inflame arterioles and capillaries in the glomerulus, resulting in vasculitis and glomerulonephritis. Tubular, non-cryoglobulinemic deposits are indicative of immunotactoid glomerulonephritis. Finally, by activating the alternative pathway, C3 glomerulonephritis can arise where a monoclonal paraprotein can act as a C3 nephritic factor.
DIAGNOSIS
MGRS is diagnosed more often in males than females with the incidence increasing after age 50 in both genders. It is important to maintain a high index of suspicion for MGRS in those with a monoclonal gammopathy, and a kidney biopsy should be considered particularly in the setting of abnormal serum free light chain ratio with either high urinary protein (>1.5 g per day), microscopic hematuria and/or rapid decline in kidney function.
MGRS ASSOCIATED BIOPSY FINDINGS
Broadly, MGRS renal findings on biopsy can be divided into two categories defined by the presence or absence of monoclonal Ig deposits. In the presence of monoclonal Ig deposits, we can further categorize the lesion into those with organized and those without organized deposits. Figure 2 below highlights the groupings, which we will delve into further.
Organized Deposits
We will first discuss organized deposits, typically recognized by size, orientation, and distribution.
Delving further into these organized deposits:
Fibrils:
Ig-related amyloidosis (AL-amyloidosis): Accounts for approximately 80% of renal amyloidosis in the US, often presenting with nephrotic range proteinuria, reduced eGFR, and systemic signs and symptoms. A disorder of the misfolding and improper metabolism of proteins, monoclonal light chains in this case, result in the circulation and systemic deposition of insoluble fibrils with notable widespread organ dysfunction. Biopsy reveals Congo red positive staining with yellow/orange/green color under polarized light, famously referred to as ‘apple green birefringence’ which is depicted in Figure 4A below. The fibrils are randomly arranged and are approximately 7-14 nm thick, non branching, and depicted in Figure 4B below. They can also appear as spicules along the glomerular capillary loops on silver stains. Renal deposition distribution includes the mesangium, GBM, vessels, tubular basement membranes, and interstitium.
Figure 4A.
Figure 4B.
Microtubules:
Immunotactoid GN: Mesangial and often proliferative GN presenting with nephrotic range proteinuria. Distinguishes itself through the deposition of hollow glomerular microtubules that are >30 nm in diameter stacked in parallel arrays. Immunofluorescence is positive for IgG and light chain, which often includes monotypic deposits. The deposits are found within the subepithelial and subendothelial zones and mesangium as well. Shown below is Figure 5:
Figure 5.
Cryoglobulins arise when proteins precipitate when temperatures are lower than 35 degrees Celsius from the serum and plasma. Cyroglobulinemia is a systemic disease due to cryoglobulins and should be considered in situations where patients may have arthralgias, purpura, glomerulonephritis; especially in chronic viral hepatitis, MM, Waldenstrom, etc).
In type 1 cryoglobulinemia GN, the cryoglobulins are usually monoclonal Igs such as more IgG or IgM and less associated with IgA or free light Ig chains. This condition is associated with multiple myeloma, Waldenstrom, or CLL. Symptoms include those of vascular occlusion due to the cryoprecipitate especially in colder temperatures. Features include intraluminal deposits which have short fibrillary appearance, at times with “fingerprint-like” structures on EM (though not to be confused with those of lupus nephritis).
Type 2 cryoglobulinemia GN should usually be considered when chronic viral infections, such as autoimmune diseases or hepatitis, are present. The cryoglobulins are a mix of monoclonal IgM and polyclonal IgG components; in most cases, the monoclonal IgM is against the Fc portion of the polyclonal IgG and is referred to as rheumatoid factor.
Type 3 cryoglobulinemia GN is actually composed of a polyclonal IgG and polyclonal IgM and are seen with autoimmune diseases and sometimes hepatitis C.
Immunofluorescence can be used to distinguish the type of cryoglobulinemia. Type 1 cryoglobulinemia has monoclonal deposits that are either IgG or IgM and are monotypic light chains. Type 2 and Type 3 usually stain for several subclasses. In type 2 cyroglobulinemia there is brighter staining for IgM and kappa than lambda and IgG which is in keeping with the type of Ig and with the monoclonal IgM found in type 2 in comparison to type 1 cryoglobulinemic GN.
The figures below highlight the duplication of the GBM, hyaline deposits and short fibril-like deposits in Figure 6A&B and Figure 7 shows the IgG staining in cryoglobulinemic GN.
Figure 6A.
Figure 7.
Crystal deposition:
Light chain proximal tubulopathy: Involves the cytoplasmic inclusion of light chain crystals within the proximal tubule. On light microscopy, rod/rhombi shaped hypereosinophilic and PAS negative crystals accumulate in the proximal tubular cells as highlighted in Figure 8.
Figure 8.
Crystal storing histiocytosis: This is a rare complication manifesting with intralysosomal accumulation of Ig within histiocytes, which affects the bone marrow and extramedullary sites like the kidney. The electron microscopy findings are shown in figure 9 which can show the rhomboid shaped dense crystals.
The biopsy reveals intracytoplasmic eosinophilic light chain crystalline inclusions within interstitial histiocytes which can be seen in the figure 10.
Figure 9.
Figure 10.
Non-organized Deposits
MIDD (Monoclonal Ig deposition disease): Manifests as linear deposits along tubular, vascular and glomerular basement membranes. It is characterized by “powdery”, electron-dense deposits along the glomerular basement membrane and tubular basement membrane.
Has three subtypes including:
LCDD (light chain deposition disease): contains monoclonal light chains only (kappa mostly).
LHCDD (light and heavy chain deposition disease): contains heavy and light chain deposition more commonly kappa and IgG.
HCDD (heavy chain deposition disease): monoclonal heavy chains more frequently gamma.
The figures below highlight MIDD. Figure 11 below shows light chain deposits along the GBM and figure 12 shows the TBM. Figure 13 highlights the Ig staining of the TBM in the HCDD.
Figure 11.
Figure 12.
Figure 13.
PGNMID (proliferative glomerulonephritis with monoclonal IgG deposits): Resembles immune complex, proliferative glomerulonephritis yet sets itself apart through demonstration of heavy staining for IgG on immunofluorescence highlighted in Figure 14. Figure 15 depicts immune deposits in the mesangial and subendothelial spaces. Figure 16 shows a negative staining of the lambda light chain seen in PGNMID.
Typically has subendothelial and mesangial granular, non-organized deposits. They lack tubular basement membrane deposits.
PGNMID has iso-monotypic immune deposits that can be either IgA, IgG, or IgM, or a light chain only variant
Figure 14.
Figure 15.
Figure 16.
Absence of Ig Deposits
In the absence of Ig deposits, C3 glomerulopathy can manifest. C3 Glomerulopathy shown below is composed of two entities: G3 glomerulonephritis (C3 GN) and dense deposit disease (DDD). Both arise due to complement activation pathway dysregulation and are notable for glomerular C3 with absent or scant IgG deposition.
C3 GN: is a mesangial proliferative, membranoproliferative, or endocapillary proliferative glomerulonephritis
DDD: sausage-like deposits that segmentally infiltrate the glomerular basement membrane lamina densa.
Figure 17.
Figure 18.
Regardless of presentation, the mainstay of treatment lies in treating the underlying cause and preventing the progression of renal failure and extrarenal features. There are no particular treatments as of yet to prevent tissue deposition or to remove pre-existing deposits. The pathological injury and the type of cellular clone (whether it is plasma cell, B cell, or lymphoplasmacytic) drive therapy. Many studies have shown that the hematological response to chemotherapies is closely linked to kidney outcomes. More studies are currently being done to compare outcomes related to specific therapeutics.
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.