What is the mechanism of kidney injury in a patient with Multiple Myeloma (MM) presenting with abdominal pain, dry mucous membranes, M protein, hyperglobulinemia (high IgG), plasma cell infiltration (>20%) in the bone marrow, impaired renal function (elevated creatinine and Blood Urea Nitrogen (BUN)), and hypercalcemia?

From the Guidelines

The mechanism of kidney injury in this multiple myeloma (MM) case is likely due to light chain cast nephropathy, as evidenced by the high M protein and IgG levels, which result in excessive light chains that interact with Tamm-Horsfall protein in the distal tubules, forming obstructive casts that block urine flow and cause tubular damage 1.

Key Mechanisms

• Light chain cast nephropathy: The overproduced monoclonal free light chain (FLC) by the myeloma cells interacts with the Tamm Horsfall protein in the loop of Henle to form light chain casts, which obstruct the tubules causing rupture and inducing an immune response that further injures the tubules 1.
• Hypercalcemia: Contributes to kidney injury by causing vasoconstriction, decreased glomerular filtration rate, and direct tubular toxicity through calcium deposition.
• Dehydration: Worsens both mechanisms by concentrating light chains and calcium in the tubules.

Treatment Approach

• Aggressive hydration with normal saline (2-3 L/day) to reduce light chain concentration and prevent further kidney damage.
• Bisphosphonates like zoledronic acid (4 mg IV) for hypercalcemia management.
• Rapid initiation of anti-myeloma therapy such as bortezomib-based regimens to reduce light chain production, as recommended by the European Myeloma Network 1.
• Plasmapheresis may be considered in severe cases with very high light chain levels to quickly reduce the circulating burden.

Important Considerations

• Serum FLC concentrations are predictive of the development of AKI and its recovery, with a minimum reduction of 50–60% of serum FLC associated with renal recovery in LCCN 1.
• A rapid reduction of serum FLC concentration is key to reversing the kidney injury, with fewer patients recovering kidney function with the same degree of FLC reduction achieved at day 21 as compared to day 12 1.

From the Research

Mechanism of Kidney Injury in Multiple Myeloma

The mechanism of kidney injury in multiple myeloma (MM) is complex and involves several factors. Key points include:

• Cast nephropathy, also known as myeloma kidney, is the most common cause of acute kidney injury (AKI) in MM patients 2, 3, 4, 5.
• Cast nephropathy occurs when filtered free light chains (FLCs) interact and aggregate with Tamm-Horsfall protein (THP) in the renal tubules, causing intratubular obstruction and damage 3, 4.
• The obstruction of distal tubules by casts of luminal proteins concentrated by intensive water reabsorption resulting from dehydration or high-dose diuretics leads to a tubular obstructive form of AKI 2.
• Reduction of circulating FLCs is thought to be associated with improved likelihood of kidney function recovery in MM patients with AKI 3, 4, 5.

Treatment and Management

Treatment and management of cast nephropathy involve:

• Rapid lowering of FLCs, which correlates with renal recovery 3.
• Clone-based therapy by reducing production and thereby precipitation of light chains 5.
• Adjuvant therapy consists of inducing high urine volume flow and alkalinisation, where possible 5.
• Extracorporeal removal of light chains, such as therapeutic plasma exchange (TPE) and extended high cutoff hemodialysis (HCO-HD), may be beneficial in some patients, but their efficacy remains uncertain 3, 4, 5.
• Modern anti-myeloma therapies, including bortezomib and anti-CD38+ monoclonal antibody, have improved outcomes in patients with myeloma cast nephropathy 6.