mieloma Flashcards
7 renal complicaçoes do MIELOMA MULTIPLO
cadeia leve ou nefropatia por cilindros
Amiloidose
dc de deposicao de cadeia leve
sindrome de fanconi
hipercalcemia com IRA
Less commonly, one might see:
Heavy chain deposition disease
Cryoglobulinemia
Uric acid nephropathy renal plasma cell invasion
Multiple myeloma
•Multiple myeloma is the malignant proliferation of plasma cells involving more than 10 percent of the bone marrow. The multiple myeloma cell produces monoclonal immunoglobulins that may be identified on serum or
urine protein electrophoresis.’
• Bone pain related to multiple lytic lesions is the most common clinical presentation.
•Multiple myeloma must be differentiated from other causes of monoclonal gammopathy, including monoclonal gammopathy of undetermined significance, heavy chain disease, plasmacytoma and Waldenstrom macroglobulinemia.
• Overproduction of light chains + tubular capacity for reabsorption is exceeded. Filtered light chains & immunoglobulins then bind Tamm-Horsfall
glycoprotein (secreted in the medullary TAL of the loop of Henle). Cast formation & obstruction in the distal nephron + resposta inflamatoria intersticial
causa mais comum de lesao renal =NEFROPATIA POR CILINDROS =RIM DO MIELOMA
aines, ieca/bra e contraste podem piorar
CRAB
Calcio, rim, anemia e bone
nefropatia por cilindros tb ocorre por macroglobulinemia de w. e LLC
bipsia= cilindros eosinofilicos geralmente fraturados dentro dos tubulos distais e cels gigantes ao redor
IF= 1 cadeia leve apenas
glomerulos poupados
proteinuria por cadeia leve=bence jones
tto= antiplasmocitos
bortezomid, cff, corticoide
NEFROPATIA POR CILINDROS
Light chain cast nephropathy (LCCN), not to be confused with light chain deposition disease (LCDD), is also known as myeloma cast nephropathy or myeloma kidney; and is one of the many renal complications of multiple myeloma. Patients affected generally have an established diagnosis of multiple myeloma and as can be expected, are typically middle aged to older adults. It is the most common histopathological finding in patients with multiple myeloma and renal dysfunction with a prevalence of 30-50%. Rarely LCCN can be the initial presentation of a subclinical or smoldering myelomatous process, and therefore this diagnosis must be high on the differential for older patients who present with acute kidney injury.
Clinical presentation
Renal dysfunction from cast nephropathy can either be acute or progressive over time and can develop at any point during the course of the disease. There can be superimposed renal disorders such as tubular dysfunction (due to direct toxicity from light chains), amyloidosis, various types of immune complex mediated disease, alternative complement pathway dysregulation etc. Proteinuria is usually nephrotic range though urinalysis is not reflective of this as the proteins consist mainly of light chains and not albumin.
How do the casts form and how do they induce injury?
Free light chains (FLC) circulating predominantly as kappa and lambda are freely filtered by the kidneys and initially reabsorbed by the proximal tubular cells (PTC) where they cause injury and PTC dysfunction. The now dysfunctional proximal tubular cells are overwhelmed by the filtered load of free light chains and allow their passage to the distal tubules where they aggregate with Tamm-Horsfall proteins (THP) secreted by the thick ascending limb (TAL) of the loop of Henle. The light chain-THP interaction leads to cast formation which in turn causes tubular obstruction as well as tubular basement membrane rupture and subsequent renal dysfunction. The presence of the casts in the tubules also elicits an inflammatory reaction and if persistent, to the rapid development of interstitial fibrosis.
What determines cast formation and renal injury?
It has been shown that inhibition of the light chain/Tamm-Horsfall protein interaction prevents cast formation. The successful interaction of the light chains and Tamm-Horsfall proteins is apparently modulated by the physiochemical features of the light chains. Specifically, the variability of the CDR3 domain of the light chains leads to varying affinity to THPs such that not all light chains successfully form casts. Volume depletion, furosemide, urinary acidification and favorable ionic environments such as high urine concentrations of sodium and calcium all promote cast formation.
Light microscopy
It is important to know the classic histologic features of light chain cast nephropathy, as in some cases the presence of LCCN may be the initial presentation of an underlying subclinical myelomatous process.
- Light chain casts have an eosinophilic appearance on H&E stain, with a pale/light pink appearance on PAS. In contrast to this TH protein casts and hyaline casts are positive on PAS, staining a bright magenta color.
It should be noted that the presence of a few monoclonal staining casts, without classic histologic features, is not enough for a diagnosis of LCCN. Classic histologic features, evidence of an active inflammatory response to the casts, and monoclonal staining should all be present in order to make this diagnosis.
Treatment
Initial management
The focus of treatment is rapid, substantial and sustained reduction in the serum FLC burden as this has been shown to promote renal recovery. In addition, factors that facilitate the precipitation of casts should be avoided or corrected if already present. Intravascular volume expansion to maintain high urine flow is important and high fluid intake (3L/day) should be maintained subsequently. Bortezomib, a reversible proteasome inhibitor, in combination with dexamethasone, for the prompt reduction of serum free light chains, is of benefit in patients with renal dysfunction as its clearance is not dependent on renal function. Immunomodulatory medications such as thalidomide, pomalidomide and lenalidomide have also been shown to be of benefit.
Additional treatment
Studies on the benefits of extracorporeal therapies have been controversial at best with some studies showing significant reduction in the burden of serum FLCs with three or more plasmapheresis sessions and others demonstrating no benefit. Studies investigating the benefit of high cut off hemodialysis (HCO-HD) have been discordant as well with some suggesting early and sustained decrease in the sFLC burden and independence from dialysis and others showing no advantage when compared to conventional dialysis. A cohort study in 2017 investigating the effectiveness of IHD with adsorptive PMMA membrane in myeloma cast nephropathy suggested high rates of renal recovery and survival and may merit further investigation.
paraptn
GAMOPATIA /PARAPROTEINEMIA
Paraprotein=o Produced by a clonal proliferation of B-cells or plasma cells. It can be composed of a light chain, heavy chain or be a complete immunoglobulin (Ig)
Monoclonal Gammopathy (MG)=o Detection of a paraprotein in the serum or urine constitutes an MG Serum and urine immunofixation tests are more sensitive than electrophoresis ->Serum free light chain (FLC) assay: Measures concentrations of both free kappa and lambda/ Highly sensitive/ Does not detect light chains attached to a heavy chain
o Can be associated with a malignant disorder (e.g., myeloma, lymphoma) or a disorder of undetermined malignancy (i.e. MGUS)
o Evaluation
Serum electrophoresis and immunofixation
24-hour urine electrophoresis and immunofixation
Serum FLC assay
Bone Marrow biopsy and aspiration
Plasma cell and B cell clonality testing is important in the workup : Plasma dyscrasias, plasmacytomas, multiple myeloma, and B-cell lymphoproliferative disorders can potentially overproduce light chains leading to AL amyloid or other paraprotein related disorders
1)Monoclonal Gammopathy of Renal Significance (MGRS)
o Kidney disorders caused by a monoclonal Igs secreted by a non-malignant or premalignant B cell or plasma cell clone that does not meet classic criteria for myeloma or a lymphoproliferative disorder= LESAO RENAL NA AUSENCIA DE MALIGNIDADE.
o Typically caused by precipitation, aggregation, crystallization or misfolding of the paraprotein at various sites of the kidney
o Differs from MGUS because of kidney damage (end-organ damage)
o Early recognition and treatment of the clone is essential in reducing the risk
for progressive kidney disease, ESRD and recurrence in the kidney allograft
Monoclonal Ig Deposition Disease
o Deposition of non-amyloid monoclonal light chains, heavy chains, or both in glomerular and tubular basement membranes
o Three subtypes
Light chain deposition disease (LCDD): Typically kappa > lambda
Pathology highlights
o Nodular glomerular sclerosis
o Classic Randall type electron-dense deposits – fine
powdery deposits, non-fibrillary
Heavy chain deposition disease (HCDD)
Less frequent than LCDD
Pathology highlights
o Nodular glomerular sclerosis
o Granular, powdery deposits; “ground pepper-like”
Light and heavy chain deposition disease (LHCDD)
Deposition of the entire monoclonal Ig
Pathology highlights
o MPGN pattern is common
o Can also see diffuse hypercellularity, crescentic
disease, and membranous
o Granular deposits without substructure
Amyloidosis
o Extracellular deposition of insoluble fibrils resulting from abnormal folding of proteins
o Various types (>30)
Ig-derived (AL, AH, AHL) most common
AA – reactive, secondary from chronic inflammation
ALECT2 – Hispanic population, diabetics
o Pathology highlights
Congo red positivity
Green birefringence under polarized light
Non-branching fibrils measuring 8-12 nm
Light Chain Tubulopathy (Crystal Storage Tubulopathy)
o Proximal RTA, Hypophosphatemia, hypouricemia, normoglycemic glycosuria o Fanconi syndrome
o AKI and potential CKD
Light Chain Cast Nephropathy
o “Myeloma Kidney”
o AKI which is typically precipitated by volume depletion, hypercalcemia or medications/drugs with vasoactive effects
C3 GN (DDD) and aHUS
o mIg acts in the fluid phase causing interference in these pathways
Amyloidosis
Extracellular deposition of insoluble fibrils resulting from proteinas mal agregadas
o Various types (>30)
Ig-derived (AL, AH, AHL)
most common= tipo de proteina amiloide AL=depoisito de cadeia leve +frequente
AL Amyloidosis: Congo-red positive on light microscopy or “apple green” birefringent on polarized light.
On silver stain ‘eye-lash” type appearance of GBM abnormalities may suggest amyloid.
Light microscopy, however, has limited sensitivity, and many cases may ultimately be diagnosed by immunofluorescence studies for immunoglobulin light chains and heavy chains.
Electron microscopy (randomly arranged non-branching microfibrils of 8-12 nm in diameter) has additional utility in diagnosis.
Predominantly lambda light chain (kappa-subtype is rare)
In U.S. most common form of amyloid (90%) (in other countries AA amyloid more common due to infection etc.)
AA – reactive, secondary from chronic inflammation= Artrite reumatoide, 2o tipo mais frequente.more common in other countries due to infection etc.
related to chronic inflammatory conditions e.g. chronic non-healing wounds, TB,,Crohn’s disease, rheumatoid arthritis, hereditary syndromes such as familial,Mediterranean fever and seen in drug users doing “skin popping” (njecting illicitdrugs into the skin).
Congo Red positive, characteristic fibrils on EM
Negative for kappa/lambda light chains on IF
ALECT2 – Hispanic population, diabetics
o Pathology highlights
Congo red positivity
Green birefringence under polarized light
nao organizadas fibrils measuring 8-12 nm
Light Chain Tubulopathy (Crystal Storage Tubulopathy)
o Proximal RTA, Hypophosphatemia, hypouricemia, normoglycemic glycosuria
o Fanconi syndrome
o AKI and potential CKD
75% dos pacientes tem proteinuria e desse 50% sindrome nefrotica
Paraprotein related kidney disease:
Can be mediated by any cell capable of producing immunoglobulins (e.g., plasma cells such as in myeloma or plasmacytoma, or B-cells such as in leukemias,lymphomas, Waldenström’s macroglobulinemia, etc.)
Due to circulating paraproteins which can:
o Deposit in tissue
Amyloid: AL, AH, AHL, AA
Non-amyloid: Monoclonal immunoglobulin deposition disease
o Be filtered by glomerulus: (e.g., cast nephropathy, crystal storing nephropathy, etc.)
o Express “functional effects” (e.g., TMA, C3 GN associated with MGRS, etc.)
Monoclonal immunoglobulin deposition disease (MIDD):
Light chain deposition disease (LCDD)
o Most common subtype /o LC only (most commonly Kappa)/o Deposits in glomeruli and tubules
Heavy chain deposition disease (HCDD)
o HC only (most commonly Gamma)/o Deposits in glomeruli and tubules/
Light and heavy chain deposition disease
o LC&HC / entire Ig (most commonly IgG3 Kappa)
o Predominantly glomerular deposits
Light microscopy (PAS, silver stain) shows nodular glomerulosclerosis (due to matrix expansion) in LCDD, HCDD
Immunofluorescence (Kappa, Lambda, Ig subclasses, C1q, C3) important to
distinguish the subtype of MIDD and differentiate from other diagnoses (e.g.
immune complex diseases)
MIDD is Congo-red negative (in contrast to amyloid)
EM shows ‘dusty’/’peppered’ deposits along GBM and TBM in LCDD, HCDD
$
Proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID):
Also referred to as “Nasr Glomerulopathy” –
Why might a urine dipstick not be positive for protein even if a patient has large amounts of light chains in their urine?
Urine dipsticks only detect albumin and not all proteins, including light chains. Therefore, a patient with multiple myeloma who has a large amount of light chains in the urine will not have a dipstick positive for albumin.
bortezomib
efeitos colaterais= mielossupressao e neuropatia periferica
