Epidemiology

• Incidence: ~200,000 new cases/year in US; 10–20 cases/million/year
• Renal involvement: 20–50% of patients at diagnosis have AKI or baseline CKD
• Clinical significance: Renal impairment = adverse prognostic factor; impacts chemotherapy dosing & prognosis

Pathophysiology of Myeloma Kidney

The mechanism (step-by-step):

1. Clonal plasma cell proliferation → Produces large amounts of monoclonal immunoglobulin (usually IgG or IgA)
2. Free light chain production → Clones make excess κ or λ light chains (>20 mg/dL)
3. Glomerular filtration → Small light chains (22 kDa) filtered by glomerulus
4. Proximal tubule uptake → Light chains reabsorbed via endocytosis
5. Tubular cast formation → Light chains precipitate with Tamm-Horsfall protein (THP) to form refractory casts
6. Tubular obstruction → Casts occlude tubular lumen → AKI
7. Interstitial inflammation → Lytic lesions trigger innate immunity
8. Result: Acute tubular necrosis + interstitial nephritis

Clinical Presentation

Diagnosis

The gold standard: Kidney biopsy

Supporting labs: - SPEP: M-spike (monoclonal paraprotein) - UPEP: Bence Jones protein (free light chains in urine) - FLC assay: ↑ Involved light chain; abnormal ratio

Management of Acute Myeloma Kidney

Medical Management:

1. Hydration: Correct depletion with fluid therapy tailored to urine output, cardiac status, and repeated assessment for overload.
2. Diuretics: Do not use furosemide routinely to force urine flow in cast nephropathy. Treat congestion only for a separate clinical indication.
3. Alkalinization: Routine urine alkalinization has no demonstrated renal recovery benefit in myeloma-related renal impairment.
4. Avoid contrast, NSAIDs: ↓ GFR further
5. Anti-myeloma therapy: Prompt initiation of chemotherapy (bortezomib, lenalidomide, etc.) → ↓ light chain production → Resolution of casts

IMWG recommendations for myeloma-related renal impairment (2023).

Renal Replacement Therapy: - Indications: Oliguric renal failure unresponsive to hydration, severe hyperkalemia, fluid overload - Modality: CRRT or hemodialysis (some argue CRRT preferred because continuous) - Outcome: 30–50% of oliguric patients recover renal function with supportive care + chemotherapy

Prognosis: - Early treatment: ~50–70% recover renal function if caught early - Delayed treatment: ~10–20% recover if AKI prolonged - Late diagnosis: Often results in permanent dialysis dependence

Long-Term Monitoring

• Serial Cr, FLC assay (response to therapy reflected in ↓ FLC)
• Suppress light chain production aggressively
• Avoid nephrotoxic drugs
• ACEi/ARB if proteinuria >1 g/day

What is MGRS?

A B-cell or plasma-cell clone produces a nephrotoxic monoclonal immunoglobulin, with related kidney injury, without otherwise meeting hematologic criteria for clone-directed treatment. Kidney injury can nevertheless require treatment. A marrow plasma-cell cutoff alone does not define MGRS.

Pathology Patterns

Examples include AL amyloidosis, monoclonal immunoglobulin deposition disease, proliferative GN with monoclonal deposits, and light-chain proximal tubulopathy. Lesions may affect glomeruli, tubules, vessels, or several compartments. Some associated lesions lack monoclonal deposits.

Clinical Presentation

Proteinuria, hematuria, tubular dysfunction, AKI, or CKD may occur. Normal blood counts do not establish or exclude MGRS.

Diagnosis

Integrate kidney biopsy, immunofluorescence and ultrastructure with serum/urine immunofixation, free light chains interpreted in kidney context, and hematologic evaluation. A monoclonal band alone does not prove renal causation.

Management

Coordinate renal and hematologic expertise for lesion- and clone-specific treatment, supportive care, and longitudinal monitoring.

IKMG consensus: definition and evaluation of MGRS (2019).

Types & Mechanisms

Clinical Features

High-grade (Burkitt, aggressive): - Peak risk: TLS (see prior handout) - AKI common (20–30% of patients) - Monitors: K+, uric acid, PO4 closely

Indolent (Low-grade): - Gradual proteinuria, hematuria - CKD progression over years - May have cryoglobulinemia (RNP, C4 ↓, Cr, mixed cryoglobulins)

Management

• Chemotherapy → Cell destruction, monitor for TLS
• Supportive: Hydration, rasburicase (if high risk)
• Renal-specific: ACEi/ARB, BP control
• Monitor: Renal function, UA, electrolytes q 1–2 weeks during/after chemotherapy

Mechanisms

AML-Specific

• Higher TLS risk if WBC >100,000 and high LDH
• Bladder involvement: Hemorrhagic cystitis (from chemotherapy)
• AKI incidence: 20–50% of hospitalized AML patients

ALL-Specific

• Highest TLS risk — ALL cells most chemosensitive
• Risk factors: Age <10 or >50, WBC >100,000, bulky disease, elevated LDH
• Management: Assess TLS risk and select prophylaxis, hydration, and monitoring accordingly; rasburicase is appropriate for selected high-risk patients with attention to G6PD safety.

Management

• Prevention: Before therapy, assess disease, treatment, and patient-specific TLS risk. Select urate-lowering treatment and hydration accordingly.
• Monitor: Baseline K+, uric acid, FLC; q6h labs during first 48 h
• Kidney replacement therapy: Escalate refractory hyperkalemia, severe acidosis, fluid overload, or uncontrolled metabolic complications. Ongoing lysis and falling urine output warrant early nephrology involvement; uric acid alone is not an automatic dialysis trigger.
• Duration: Usually 5–7 days of intensive monitoring

Timing & Complications

Acute Kidney Injury in SCT

Incidence: 40–50% of SCT patients develop AKI; 10–15% require dialysis

Causes: - Chemotherapy nephrotoxicity (conditioning regimens contain high-dose cyclophosphamide, busulfan) - Sepsis (immune reconstitution not complete; infection risk high) - Aminoglycoside antibiotics (empiric for fever) - Amphotericin B (fungal prophylaxis) - Calcineurin inhibitors (graft-versus-host disease prophylaxis) - TLS (from rapid leukemic cell kill if allogeneic transplant for hematologic malignancy)

Chronic Kidney Disease in SCT

Long-term renal outcomes: - 5-year CKD incidence: 20–30% - Risk factors: High-dose conditioning, older age, GVHD, multiple nephrotoxic drugs, TBI (total body irradiation) - Mechanism: CNI toxicity (cyclosporine/tacrolimus) → Hyaline arteriosclerosis, glomerulosclerosis, tubular atrophy

Management Strategies

Prevention: - Minimize CNI exposure; use lowest effective dose - Alternate CNIs with sirolimus if tolerated - Avoid concurrent nephrotoxic drugs (NSAIDs, contrast agents) - Monitor BP closely (control with ACEi/ARB)

Monitoring: - Baseline renal function before conditioning - Daily Cr during conditioning & early engraftment (first 30 days) - q 1–2 week labs during months 1–3 - q 1–3 month labs long-term (look for CKD progression)

Management of AKI: - Discontinue nephrotoxic drugs if possible - Hydration (unless fluid overloaded from sepsis/capillary leak) - RRT if oliguric or severe electrolyte derangements - Empiric antibiotics with renal dosing

Management of CKD: - ACEi/ARB to slow progression - BP target <130/80 (2025 AHA/ACC, ADA); KDIGO 2021 suggests systolic <120 on standardized measurement - Reduce CNI to lowest dose; consider switch to alternative agent - Avoid NSAIDs - Monitor for bone disease (CKD-MBD from chronic GFR reduction)

Red Flags

• ✗ Myeloma patient with rapid ↑ Cr → Urgent evaluation for cast nephropathy; assess perfusion and congestion while arranging disease-directed treatment.
• ✗ High-grade lymphoma with rising potassium, phosphate, uric acid, or AKI → Evaluate urgently for TLS.
• ✗ AML with WBC >100k → Highest TLS risk; ICU-level monitoring
• ✗ SCT day +5 with ↑ Cr → Could be chemo, sepsis, CNI toxicity, or TLS overlap

Key Interventions by Scenario