What is myeloma kidney?

What is Myeloma Kidney?

Myeloma kidney, also known as cast nephropathy, is a medical emergency characterized by acute kidney injury caused by excessive monoclonal free light chains that precipitate with Tamm-Horsfall protein in the distal tubules, forming obstructive casts that cause tubular rupture, obstruction, and progressive interstitial inflammation and fibrosis. 1, 2

Pathophysiology

The mechanism of kidney damage in myeloma kidney involves two primary pathways:

Distal Tubule Cast Formation

• Excessive immunoglobulin free light chains (FLCs) overwhelm the normal reabsorptive capacity of proximal tubules and reach the distal tubules, where they bind to Tamm-Horsfall protein and co-precipitate to form obstructive casts. 1, 3
• These casts cause tubular obstruction, leading to tubular atrophy proximal to the cast and progressive interstitial inflammation and fibrosis. 1
• Cast nephropathy is the most frequent form of renal damage in multiple myeloma, accounting for approximately 90% of cases. 1

Direct Proximal Tubular Toxicity

• High concentrations of FLCs in the ultrafiltrate directly injure proximal tubular cells through activation of redox pathways, with increased expression of NFκB and MAPK. 1, 3
• This activation leads to production of hydrogen peroxide and transcription of inflammatory and profibrotic cytokines (including CCL2, IL-6, TGF-β1), resulting in tubular cell death. 1

Risk Stratification

Serum FLC concentrations >50 mg/dL significantly increase the risk of acute kidney injury, with risk dramatically increasing when FLC levels exceed 80-200 mg/dL. 2, 3

Clinical Presentation and Diagnosis

Defining Renal Impairment

• Renal impairment in multiple myeloma is defined by eGFR <40 mL/min/1.73 m² or serum creatinine >2 mg/dL, which represents one of the 'CRAB' diagnostic criteria for symptomatic myeloma. 1, 3
• Mild renal impairment (eGFR <60 mL/min/1.73 m²) can be observed in 25-50% of patients during the course of their disease. 1

Diagnostic Workup

• Measure serum creatinine, electrolytes, eGFR (using MDRD or CKD-EPI formula), 24-hour urine collection with electrophoresis and immunofixation, and serum free light chains. 1, 2, 4
• The International Myeloma Working Group recommends using the MDRD equation for estimating GFR, though CKD-EPI formulas (particularly with cystatin C) provide improved prognostic ability. 1, 3
• If proteinuria consists mainly of light chains with high serum FLC levels, renal biopsy is probably not necessary. 1, 2
• Renal biopsy should be considered when other conditions (diabetes, chronic hypertension) are present or when the etiology is unclear. 1, 4

Other Mechanisms of Renal Damage

Beyond cast nephropathy, several other processes contribute to kidney injury:

• Light chain deposition disease (LCDD) and AL amyloidosis occur when monoclonal light chains deposit in kidney tissue or form amyloid fibrils. 1, 3
• Fanconi's syndrome can result from functional impairment of proximal tubule reabsorptive capacity, characterized by glucosuria, aminoaciduria, and hypophosphatemia. 1
• Contributing nephrotoxic factors include dehydration, hypercalcemia, hyperuricemia, infections, and nephrotoxic medications (particularly NSAIDs). 1

Management Principles

Immediate Interventions

Myeloma kidney should be treated as a medical emergency requiring adequate hydration, urine alkalinization, treatment of hypercalcemia, discontinuation of nephrotoxic medications, and prompt anti-myeloma therapy. 1, 3

Antimyeloma Therapy

• Bortezomib-based regimens should be initiated immediately as first-line therapy because they do not require dose adjustment in renal impairment, are not nephrotoxic, and can be safely used in dialysis patients. 2, 3, 5
• The goal is to achieve at least 50-60% reduction in FLC levels by day 12 of treatment, with a target FLC level <50 mg/dL by the end of cycle 1. 2, 3
• Bortezomib-based regimens can result in rapid reversal of renal failure in up to 50% of patients. 5, 6

Extracorporeal Therapies

• For patients with FLC >150 mg/dL, daily plasma exchange or high cut-off hemodialysis should be added to chemotherapy. 2
• Plasma exchange can reduce serum FLC levels by 45-75% per session, while high cut-off hemodialysis can remove 60-75% of FLCs per session. 2

Prognosis

• Renal recovery is associated with improved overall survival, with factors predicting recovery including lower baseline creatinine and ≥50% reduction in serum FLC levels. 2, 3
• Achieving serum FLC concentration <50 mg/dL by the end of cycle 1 and earlier FLC reduction (by day 12 vs. day 21) improve renal recovery rates. 3
• Despite advances in therapy, patients without kidney recovery have higher early mortality. 2

Common Pitfalls

• Avoid using serum creatinine alone to assess renal function; always calculate eGFR using validated equations (MDRD or CKD-EPI). 1
• Do not delay antimyeloma therapy while awaiting renal biopsy results when clinical presentation strongly suggests cast nephropathy. 2
• Remember that lenalidomide requires dose adjustment based on renal function, whereas bortezomib does not. 2
• In severe renal impairment (CKD stage 5), the normal κ:λ FLC ratio can rise to 0.34-3.10, which must be considered when interpreting results. 4