Paraprotein-Related Disorders Flashcards
Paraprotein-Related Disorders
Epidemiology
Multiple Myeloma and the Kidney
Kidney involvement is common:
40% of patients present with SCr > 1.5 mg/dL.
Paraprotein-Related Disorders
Epidemiology
Survival is associated with kidney function following treatment of multiple myeloma.
Paraprotein-Related Disorders
Renal Manifestations (Combination of Lesions May Be Present in Same Patient)
Tubular involvement:
Light-chain (Bence Jones) cast nephropathy a.k.a. “myeloma kidney”:
Most common renal presentation (40% to 60%) in association with elevated SCr
Paraprotein-Related Disorders
Renal Manifestations (Combination of Lesions May Be Present in Same Patient)
Tubular involvement:
Pathogenesis: acute or chronic kidney injury due to filtration of toxic light chains leading to tubular injury and intratubular cast formation and obstruction.
Paraprotein-Related Disorders
Renal Manifestations (Combination of Lesions May Be Present in Same Patient)
Tubular involvement:
Histopathology: LM: Light chain casts which are angulated, fractured or coarsely granular staining orange on Masson trichrome and PAS negative in distal tubules. Casts are often surrounded or engulfed by multinucleated giant cells. IF: casts stain strongly for the abnormal light chain, with minimal staining for other immune reactants.
Paraprotein-Related Disorders
Renal Manifestations (Combination of Lesions May Be Present in Same Patient)
Tubular involvement:
Associated with “proteinuria mismatch.” Proteinuria from cast nephropathy arises from the large amount of filtered free light chains (FLC) “Bence Jones protein,” which, unlike albumin, are not well detected by the routine urinalysis dipstick. That is, while a urine dipstick may indicate “trace” or “1+” proteinuria, the actual quantification of proteinuria from a 24-hour urine collection or uPCR would be equivalent to “≥3+” proteinuria.
Paraprotein-Related Disorders
Renal Manifestations (Combination of Lesions May Be Present in Same Patient)
Tubular involvement:
Proteinuria mismatch may also be unmasked by the addition of sulfosalicylic acid (SSA) to the urine sample because SSA precipitates all proteins including all albumin as well as light chains.
Paraprotein-Related Disorders
Renal Manifestations (Combination of Lesions May Be Present in Same Patient)
Tubular involvement:
Fanconi syndrome: proximal tubular injury due to the reabsorption and accumulation of crystallized nondegradable toxic variable domain fragments of the filtered light chains. Patients may present with various proximal tubular transport defects including proximal renal tubular acidosis, phosphate wasting, uricosuria (hence hypouricemia), euglycemic glucosuria, and aminoaciduria.
Paraprotein-Related Disorders
Renal Manifestations (Combination of Lesions May Be Present in Same Patient)
Tubular involvement:
Histopathology: LM: Crystalline inclusions (stain as light blue on H&E) with tubular damage may be seen in proximal tubular cells. EM: proximal tubular cells are filled with electron-dense light-chain crystals with needle, rod, rhomboid, or rectangular shapes
Paraprotein-Related Disorders
Renal Manifestations (Combination of Lesions May Be Present in Same Patient)
Tubular involvement:
Distal tubular dysfunction
Paraprotein-Related Disorders
Renal Manifestations (Combination of Lesions May Be Present in Same Patient)
Interstitial involvement:
Plasma cell infiltration
Interstitial nephritis
Paraprotein-Related Disorders
Glomerular involvement:
Primary amyloidosis (20% to 30%), (AL, ALH, or rarely AH)
Two-third of cases are from λ-light chains
Light chains are partially metabolized in macrophages then secreted. The metabolized fragments may precipitate into granular deposits and β-pleated fibrils as “amyloid,” which is Congo-red positive.
Paraprotein-Related Disorders
Glomerular involvement:
Primary amyloidosis (20% to 30%), (AL, ALH, or rarely AH)
Amyloid depositions within the kidney leading to extensive mesangial and GBM injury can manifest as significant albuminuria and nephrotic range proteinuria. Since routine urinalysis with a dipstick can detect albuminuria well, “proteinuria mismatch” is not characteristic of renal amyloidosis in contrast to that seen in myeloma kidney/cast nephropathy.
Paraprotein-Related Disorders
Glomerular involvement:
Primary amyloidosis (20% to 30%), (AL, ALH, or rarely AH)
In the case of predominant interstitial and vascular involvement, progressive kidney injury occurs but with minimal proteinuria.
Paraprotein-Related Disorders
Glomerular involvement:
Monoconal Immunoglobulin Deposition Disease (MIDD) involves the deposition of monoclonal light chain (80%), and less commonly heavy chain (10%), or both (10%) in the mesangium and tubular and GBMs.
Monoclonal κ-light chain is most common with MIDD (two-third of cases)
Paraprotein-Related Disorders
Glomerular involvement:
Monoconal Immunoglobulin Deposition Disease (MIDD) involves the deposition of monoclonal light chain (80%), and less commonly heavy chain (10%), or both (10%) in the mesangium and tubular and GBMs.
Same pathogenesis as amyloidosis, but light chain fragments in this case do not form β-pleated fibrils and are Congo red negative.
Paraprotein-Related Disorders
Glomerular involvement:
Monoconal Immunoglobulin Deposition Disease (MIDD) involves the deposition of monoclonal light chain (80%), and less commonly heavy chain (10%), or both (10%) in the mesangium and tubular and GBMs.
As GBM is affected and significant albuminuria can occur, MIDD does not present with proteinuria mismatch.
Paraprotein-Related Disorders
Glomerular involvement:
Others: MPGN, monoclonal cryoglobulinemia, proliferative GN with monoclonal Ig deposits (PGNMID), intraglomerular IgM deposits with resultant thrombi formation (Waldenstroms macroglobulinemia), immunotactoid GN, fibrillary GN, and rarely MCD.
MPGN associated with monoclonal gammopathy often presents with both IgG and C3 deposits, or less commonly, IgM and C3 deposits. Rarely, some monoclonal Ig proteins and/or their fragments can inhibit complement alternative pathway regulatory proteins (CfH or C3Bb) and induce a “complement-only” form of GN.
Paraprotein-Related Disorders
Glomerular involvement:
Others: MPGN, monoclonal cryoglobulinemia, proliferative GN with monoclonal Ig deposits (PGNMID), intraglomerular IgM deposits with resultant thrombi formation (Waldenstroms macroglobulinemia), immunotactoid GN, fibrillary GN, and rarely MCD.
Older patients with C3GN should therefore also be evaluated for a monoclonal gammopathy.
Paraprotein-Related Disorders
Glomerular involvement:
Others: MPGN, monoclonal cryoglobulinemia, proliferative GN with monoclonal Ig deposits (PGNMID), intraglomerular IgM deposits with resultant thrombi formation (Waldenstroms macroglobulinemia), immunotactoid GN, fibrillary GN, and rarely MCD.
PGNMID and immunotactoid GN may present with hypocomplementemia in 1/3 of cases.
Paraprotein-Related Disorders
Glomerular involvement:
Others: MPGN, monoclonal cryoglobulinemia, proliferative GN with monoclonal Ig deposits (PGNMID), intraglomerular IgM deposits with resultant thrombi formation (Waldenstroms macroglobulinemia), immunotactoid GN, fibrillary GN, and rarely MCD.
Immunotactoid GN is much more commonly associated with monoclonal gammopathy/lymphoproliferative disease than fibrillary GN.
Paraprotein-Related Disorders
Glomerular involvement:
Others: MPGN, monoclonal cryoglobulinemia, proliferative GN with monoclonal Ig deposits (PGNMID), intraglomerular IgM deposits with resultant thrombi formation (Waldenstroms macroglobulinemia), immunotactoid GN, fibrillary GN, and rarely MCD.
Fiber size difference: Amyloid fibrils are smallest with diameter 10 nm, fibrillary fibrils are 15 to 25 nm, immunotactoid microtubules are 30 to 50 nm and cryoglobulin microtubules are 20 to 30 nm.
Paraprotein-Related Disorders
Glomerular involvement:
Others: MPGN, monoclonal cryoglobulinemia, proliferative GN with monoclonal Ig deposits (PGNMID), intraglomerular IgM deposits with resultant thrombi formation (Waldenstroms macroglobulinemia), immunotactoid GN, fibrillary GN, and rarely MCD.
Electron microscopy: amyloidosis, fibrillary immunotactoid and cyroglobulin fibrils/microtubules
Paraprotein-Related Disorders
Other complications associated with paraproteinemia:
Hypercalcemia: nephrocalcinosis, interstitial nephritis, reduced renal perfusion due to hypercalcemia induced vasoconstriction, intratubular calcium salt precipitations.
Paraprotein-Related Disorders
Other complications associated with paraproteinemia:
Hyperuricemia: acute uric acid nephropathy, interstitial nephritis
Paraprotein-Related Disorders
Other complications associated with paraproteinemia:
Light-chain deposition in muscle leading to rhabdomyolysis
Paraprotein-Related Disorders
Other complications associated with paraproteinemia:
Hyperviscosity syndrome:
Associated with excessive formation of abnormal polymers of IgA or IgG3 or κ-light chains
Paraprotein-Related Disorders
Other complications associated with paraproteinemia:
Hyperviscosity syndrome:
Clinical manifestations: blurred vision, neurologic symptoms, confusion, oral/nasal bleeding, heart failure, kidney injury/acute tubular necrosis
Paraprotein-Related Disorders
Other complications associated with paraproteinemia:
Hyperviscosity syndrome:
Treatment: plasmapheresis if obvious symptoms regardless of serum viscosity index. Serum viscosity index may not correlate well with symptoms.
Paraprotein-Related Disorders
Other complications associated with paraproteinemia:
Volume depletion:
Hypercalcemia-induced nephrogenic diabetes insipidus
Reduced oral intake
Cardiomyopathy (e.g., amyloid involvement)
Paraprotein-Related Disorders
Other complications associated with paraproteinemia:
Treatment related:
Drugs (NSAIDS), antibiotics
Use of intravenous contrast dye with computed tomography
Paraprotein-Related Disorders
Other complications associated with paraproteinemia:
Treatment related:
Bisphosphonates (zolendronate: acute tubular necrosis; pamidronate, zolendronate: FSGS)
Paraprotein-Related Disorders
Diagnosis
Nonspecific clues suggesting the possibility of paraproteinemia, multiple myeloma:
Urine studies:
Routine urinalysis is typically “bland.”
Urine-free light chains > 1,500 mg/L, proteinuria mismatch, and low percentage of albuminuria compared to total proteinuria indicate myeloma cast nephropathy.
Glucosuria in the absence of hyperglycemia; phosphaturia; renal tubular acidosis
Paraprotein-Related Disorders
Diagnosis
Nonspecific clues suggesting the possibility of paraproteinemia, multiple myeloma:
Chemistries:
Low to positive serum anion gap
Hypercalcemia
Paraprotein-Related Disorders
Diagnosis
Nonspecific clues suggesting the possibility of paraproteinemia, multiple myeloma:
Chemistries:
Hyperphosphatemia out of proportion to degree of kidney failure if high levels of serum FLC as they may give falsely high phosphate levels
Paraprotein-Related Disorders
Diagnosis
Nonspecific clues suggesting the possibility of paraproteinemia, multiple myeloma:
Chemistries:
High serum total protein to albumin ratio
Low complements in PGNMID and immunotactoid GN
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
Serum (or urine) protein electrophoresis (SPEP or UPEP): SPEP separates serum proteins into five general regions in the order of albumin, α1, α2, β, and γ based on their charge and size.
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
The various immunoglobulin classes (IgG, IgA, IgM, IgD, and IgE) are usually of γ mobility, but they may also be found in the β-γ and β regions, and occasionally extend into the α2-globulin area.
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
An “M”-spike indicates the presence of a “M”onoclonal protein. Each M-protein consists of two heavy polypeptide chains of the same class: γ (IgG: IgG1-IgG4), α (IgA: IgA1, IgA2), µ (IgM), δ (IgD), ε (IgE).
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
The paired heavy chains are associated with two light chains of the same type (κ or λ), not both.
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
“Polyclonal gamma globulin” on SPEP does not indicate a monoclonal gammopathy, but a polyclonal immunoglobulin production in response to various conditions including liver disease, connective tissue, nonspecific inflammatory disorders.
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
SPEP is a useful screening procedure but it may miss a small M-protein spike or falsely identify a polyclonal increase in Ig or non-Ig as an M-protein spike. Identification of the actual makeup of the M-protein requires immunofixation.
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
In serum (or urine) protein immunofixation electrophoresis (IFE), antibodies directed against the heavy and light chains (anti-γ, anti-mu, anti-α [IgG, M, A] and anti-κ and anti-λ) are added following the initial electrophoresis procedure to identify overproduction of any corresponding chain.
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
Direct assay for serum-free light chain (Bence Jones) is more sensitive in establishing the diagnosis of monoclonal gammopathy than either SPEP or IFE. However, it must be noted that the quantity of both κ and λ light chains may be increased with poor kidney function due to reduced renal excretion.
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
The abnormal ratio of κ to λ light chains (i.e., outside the range of 0.26 to 1.65 for normal kidney function and 0.37 to 3.1 for poor kidney function) better serves to indicate a monoclonal gammopathy in patients with advanced CKD than the actual quantity of κ and λ light chains.
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
NOTE: Serum-free light chain assay is particularly important in the diagnosis of nonsecretory myeloma, AL amyloidosis (patients with amyloidosis may not have active myeloma), and light-chain-only myeloma.
Paraprotein-Related Disorders
Diagnosis
Testing options for monoclonal gammopathy:
Evaluation of suspected monoclonal gammopathy (International Myeloma Working Group):
- Serum protein electrophoresis with immunofixation
- 24-hour urine protein electrophoresis
- Serum FLC
Paraprotein-Related Disorders
Histopathology
Amyloidosis
LM: Amyloid stains as silver and PAS negative material in mesangial regions and/or capillary walls. It is Congo red positive and displays apple green birefringence when viewed with polarized light
Paraprotein-Related Disorders
Histopathology
Amyloidosis
IF: Smudgy amorphous staining for the appropriate light and/or heavy chain. If it is a non-AL amyloid (AA amyloid, transthyretin, Lect2, fibrinogen Aα), there is no light chain or immunoglobulin staining.
Paraprotein-Related Disorders
Histopathology
Amyloidosis
EM: 10 nm haphazardly arranged fibrils.
Paraprotein-Related Disorders
Histopathology
Monoclonal immunoglobulin deposition disease (MIDD)
LM: Glomeruli may appear nodular identical to diabetic glomerulosclerosis, mesangial proliferative, crescentic or normal
Paraprotein-Related Disorders
Histopathology
Monoclonal immunoglobulin deposition disease (MIDD)
IF: Diffuse strong linear staining of all renal basement membrane and extracellular material for the abnormal light and/or heavy chain.
Paraprotein-Related Disorders
Histopathology
Monoclonal immunoglobulin deposition disease (MIDD)
EM: Coarse granular electron dense material along/within glomerular and tubular basement membranes.
Paraprotein-Related Disorders
Management
Volume repletion with normal saline is key.
Management of hypercalcemia:
Administration of normal saline as safely tolerated
Paraprotein-Related Disorders
Management
Volume repletion with normal saline is key.
Management of hypercalcemia:
Corticosteroids ± bisphosphonates (pamidronate > zolendronate (due to dosing problem with severe kidney failure in the latter; calcitonin if refractory to bisphosphonates or rapid calcium reduction is needed).
Paraprotein-Related Disorders
Management
Volume repletion with normal saline is key.
Management of hypercalcemia:
Hemodialysis if severe hypercalcemia (serum calcium > 18 mg/dL)
Paraprotein-Related Disorders
Management
Avoid contrast studies, NSAIDS, nephrotoxic medications
Paraprotein-Related Disorders
Management
Chemotherapy for underlying multiple myeloma, common regimens:
Bortezomib (Velcade, proteasome inhibitor) + CYC + dexamethasone
Bortezomib + melphalan + prednisone
Paraprotein-Related Disorders
Management
Chemotherapy for underlying multiple myeloma, common regimens:
Lenalidomide (Revlimid) + dexamethasone
Melphalan + prednisone + thalidomide
Paraprotein-Related Disorders
Management
Chemotherapy for underlying multiple myeloma, common regimens:
Thalidomide + dexamethasone
Bortezomid + lenalidomide + dexamethasone
Paraprotein-Related Disorders
Management
Chemotherapy for underlying multiple myeloma, common regimens:
Reduction of serum FLC with chemotherapy predicts renal response in multiple myeloma. Plasma exchange has not been shown to improve kidney function in MM.
Paraprotein-Related Disorders
Management
Treatment of AL amyloidosis:
Nonmyeloablative chemotherapy and autologous stem cell transplantation (ASCT)
Preferred therapy, but high risk of serious complications
Paraprotein-Related Disorders
Management
Treatment of AL amyloidosis:
Nonmyeloablative chemotherapy and autologous stem cell transplantation (ASCT)
Criteria of eligibility for ASCT: NT-probrain natriuretic peptide < 5,000 ng/mL, troponin T < 0.06 ng/mL, age < 70 years, <3 organs involved, SCr < 1.7 mg/dL
Paraprotein-Related Disorders
Management
Treatment of AL amyloidosis:
Triple therapy if cannot tolerate ASCT:
CYC + thalidomide (or lenalidomide or bortezomib) + dexamethasone
Melphalan + lenalidomide + prednisone
Paraprotein-Related Disorders
Management
Treatment of AL amyloidosis:
Triple therapy if cannot tolerate ASCT:
Double therapy if cannot tolerate triple therapy: oral melphalan and dexamethasone
Paraprotein-Related Disorders
Management
Treatment of AL amyloidosis:
Dialysis support as necessary
Plasmapheresis in the presence of hyperviscosity
Paraprotein-Related Disorders
Other Fibrillary Disorders
Fibronectin GN: autosomal-dominant disorder associated with massive deposition of fibronectin.
Paraprotein-Related Disorders
Other Fibrillary Disorders
Collagenofibrotic (collagen III) GN: GN associated with massive accumulation of atypical type III collagen fibrils in mesangium and subendothelial space
Paraprotein-Related Disorders
Other Fibrillary Disorders
Nail–patella syndrome and hereditary multiple exostoses syndrome (or hereditary multiple osteochondromas syndrome) with nephrotic syndrome and associated glomerular fibrillar collagen deposition
