nephrology

1. AETIOLOGY AND MANAGEMENT OF ACUTE KIDNEY
INJURY IN MULTIPLE MYELOMA
BEN SPRANGERS
NEPHROLOGY DIALYSIS TRANSPLANTATION-2018

2. REVISED INTERNATIONAL MYELOMA WORKING GROUP DIAGNOSTIC
CRITERIA FOR MULTIPLE MYELOMA AND SMOULDERING MULTIPLE
MYELOMA (2014)
 Clonal bone marrow plasma cells ≥10%
or
biopsy-proven bony or extramedullary plasmacytoma*
and
any one or more of the following myeloma defining events:
• Hypercalcaemia: serum calcium >0·25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2·75
mmol/L (>11 mg/dL)
• Renal insuffi ciency: creatinine clearance 177 μmol/L (>2 mg/dL)
• Anaemia: haemoglobin value of >2 g/dL below the lower limit of normal, or a haemoglobin value <10g /dl
• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
• Involved:uninvolved serum free light chain ratio ≥100, or involved free light chain concentration >10m/dl

3. OR
NONE OF THE ABOVE
BUT
Clonal bone marrow plasma cell percentage* ≥60%

4. EPIDEMIOLOGY
 Nearly 20% of patients have a serum creatinine concentration greater than 2.0 mg/dL,
 10% of patients require dialysis on presentation.
 Recovery of renal function occurs in fewer than 25% of patients who require dialysis.
 AKI is associated with higher mortality, but this may be reflective of more advanced disease in these
patients

5. CAUSES
mIg INDEPENDENT FACTORS
 volume depletion
 hypercalcaemia,
 hyperuricaemia,
 nephrotoxic agents [radiocontrast agents, non-steroidal anti-inflammatory drugs (NSAIDs) and renin–
angiotensin system inhibitors]
 sepsis
 rhabdomyolysis.

6. SPECTRUM OF RENAL INVOLVEMENT
 Cast nephropathy
 light-chain deposition disease
 AL amyloidosis.
 Cryoglobulinemia
 proliferative glomerulonephritis
 heavy chain deposition disease
 immunotactoid glomerulonephritis

7. PATHOPHYSIOLOGY

8. Renl clearance of
kappa=lambda
Kappa/lambda -0.37-3.17

9. CAST NEPHROPATHY
Increased IL6,IL8,CCL2,TGFβ2
• Interact with Tamm Horsfall protein
and precipitatecasts
Progressive interstitial
inflammation and fibrosis

10. CAST NEPHROPATHY
 Most common cause of AKI
 Excess light chains precipitate with Tamm-Horsfall mucoprotein secreted by the thick ascending limb of the loop of Henle
and produce casts in the distal tubule.
 ADD on triggers-hypercalcemia, volume depletion, diuretics, and nonsteroidal anti-inflammatory drugs
 Clinical features-
 elderly patient with unexplained renal failure, anemia, and bone pain
 Subnephrotic proteinuria
 Histologically, casts are eosin positive, fractured, and waxy in appearance on light microscopy. ,Multinucleated giant cells
surrounding casts, and an interstitial inflammatory infiltrate  Widespread tubular atrophy and interstitial fibrosis
 Immunofluorescence stain-light-chain restriction within the casts. The glomeruli and vessels appear normal, unless light-
chain deposition disease is concurrently present.
 diagnosis of light chain CN can be made presumptively if the circulating FLC levels are high (>500mg/L) in the presence of
MM and AKI

11. Casts have a lattice-like appearance having needle-shaped crystals on electron microscopy

13. LIGHT CHAIN DISEASE
 Clinical features- Nephroticrange proteinuria, Hypertension, microscopic hematuria
 hallmark-development of mesangial nodules secondary to the upregulation of PDGF-β and TGF-β
 Nodular sclerosing glomerulopathy

15. • On light microscopy, mesangial nodules more uniform in distribution and size than in diabetic nephropathy
• Irregular thickening and double contours of the glomerular basement membrane may also be present
• Eosin-positive deposits may be seen diffusely throughout tubular basement membranes
• Immunofluorescence studies-characteristic linear staining of basement membranes with monotypic light
chains, which are most commonly κ restricted.
• On electron microscopy, granular powder deposits are distributed within the mesangium and midportion of the
glomerular, tubular, and vessel wall basement membrane

16. AL AMYLOIDOSIS
 AL amyloidosis occurs when pathogenic light chains unfold and deposit as insoluble fibrils extracellularly
within tissues
 Nephrotic syndrome

19. PROXIMAL RTA
 One of the most common cause of acquired proximal RTA in adults
 increased excretion immunoglobulin light chains injures the proximal tubule epithelium
 light chains in multiple myeloma have variable domain resistant to degradation by proteases in
lysosomes in proximal tubule cells.
 Accumulation of the variable domain fragments may be responsible for the impairment in tubular
function

20. OTHER CAUSES
 acute tubular necrosis (ATN) secondary to sepsis or nephrotoxic antiinfective drugs, tumor lysis
syndrome after therapy
 Hyperviscosisty syndrome
 Osteoclast-mediated bone destruction  hypercalcemia ATN,interstitial nephritis, nephrogenic
diabetesinsipidus, or nephrolithiasis.
 Tubular damage from the lightchain depositsnephrogenic diabetes insipidus.
 Rarely, malignant plasma cells may directly invade the kidney AKI
 Hyporeninemic hypoaldosteronism

21. MANAGEMENT
 Correction of hypercalcemia , aggressive hydration, alkalinisation of the urine
 Avoidance of nonsteroidal antiinflammatory drugs and intravenous radiocontrast agents.
 Steroids may be utilized to acutely decrease the burden of circulating light chains until more definitive
chemotherapy can begin
 Reduction of FLC levels can be obtained by the rapid initiation of cytotoxic chemotherapy and by
performing plasmapheresis/high cut-off haemodialysis (HCO-HD).
 Studies of the effectiveness of plasmapheresis in the treatment of myeloma cast nephropathy have
yielded conflicting results

22. VISTA TRIAL
 Velcade as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and Prednisone
(VISTA) trial
 compared the efficacy of bortezomib plus melphalan and prednisone (VMP) and melphalan and
prednisone (MP) in previously untreated MM-CN patients with renal impairment.
 Renal impairment reversal [baseline glomerular filtration rate (GFR) <50 improving to >60mL/min/1.73
m2]
 seen in 44% of VMP-treated patients versus 34% of MP-treated patients.
 Younger age and less severe impairment at baseline were identified as predictors of renal impairment
reversal

23. DIALYSIS/PLASMAPHARESIS
 7% MM patients will present with dialysis dependent AKI
 role of plasmapheresis or HCO-HD to remove FLC in these patients is controversial.
 randomized trials indicate a lack of benefit.
 In a recent French randomized clinical trial (MYRE)- HCO-HD compared with conventional HD did not
result in a statistically significant difference in HD independence at 3months
 Eulite Trial there was no difference in dialysis independence at 3 months in patients treated with HCO-
HD compared with conventional HD and also there were significantly more episodes of lung infection in
the HCO-HD group.
 Therefore, we recommend plasmapheresis/HCO-HD only in the context of trials.

24.  Survival is reduced to <1 year in MM patients with AKI who do not recover renal function
 reversibility of MM-associated AKI is an important predictor of patient survival