By Jon Emile Kenny, MD
Faculty Peer Reviewed
“You mean I’ve got cancer and my kidneys are failing, doc?” said my frail patient on the Bellevue oncology service shortly after a medical student had told him that his kidneys were damaged. Indeed, his new diagnosis of multiple myeloma was accompanied by an admission creatinine of 2.5 mg/dL.
About a quarter of patients with multiple myeloma have renal insufficiency at diagnosis . There are a number of clinicopathologic responses to multiple myeloma that occur within the kidney and most often result in a condition termed myeloma kidney, which is specifically caused by a combination of myeloma cast nephropathy and inflammatory cascades triggered by the presence of light chains within the nephron tubules. In addition to myeloma kidney, renal function in multiple myeloma may become compromised by hypercalcemia, acquired Fanconi syndrome, light chain deposition disease, and light-chain associated amyloidosis .
Myeloma Kidney. Light chain proteins are normally freely filtered by the glomerulus and are later endocytosed within the proximal tubule and returned to the bloodstream . In multiple myeloma, this mechanism of removal becomes overwhelmed and the light chains instead form aggregates with Tamm-Horsfall protein in the distal tubule. The hypervariable region of the light chain is primarily responsible for this interaction . Eventually the aggregate protein casts obstruct urinary flow and reduce the glomerular filtration rate . Furthermore, light chain endocytosis itself triggers numerous pro-inflammatory signaling cascades, such as the NF-kappaB pathway  and with long-standing inflammatory changes comes excessive interstitial fibrosis and impaired tubular function .
Hypercalcemia. Multiple myeloma is associated with excessive osteoclast-mediated bone destruction and resultant hypercalcemia (8), which in turn leads to afferent arteriolar constriction in the kidney and also overall volume depletion. Together, these mechanisms enhance cast formation and also independently worsen the already tenuous renal function in those patients with multiple myeloma .
Fanconi Syndrome. Humans produce two types of light chains: kappa and lambda. In particular, kappa light chains can wreak damage on the proximal renal tubules  and cause Fanconi syndrome. This condition describes a failure in the resorptive capability of the proximal tubules and results in type II renal tubular acidosis, glycosuria, aminoaciduria, hypophosphatemia, and hypouricemia .
Systemic disorders. Finally, light-chain deposition disease (LCDD) and light-chain associated amyloidosis (AL) are both systemic disorders characterized by tissue deposition of excess proteins—immunoglobulin light chains in LCDD and fibrillar structures from the N-terminal fragments of light chain variable regions in AL . Because the glomeruli are responsible for filtering light chain proteins, the kidney is a prominent target for both light chain and N-terminal fragment deposition. Not surprisingly, kidney involvement usually dominates the clinical course of LCDD . The light chains and their fragments usually deposit themselves within the mesangium of the glomerulus, but may also be present in the arterioles and capillaries . Furthermore, light chains and N-terminal fragments alter the biochemistry of the human mesangial cell in different ways, which can be demonstrated under the microscope by Congo red staining . The N-terminal fragments of AL bind intensely to the Congo red stain, causing a characteristic apple-green birefringence, while light chains do not .
Renal failure secondary to hypercalcemia or volume depletion may resolve with the appropriate treatment. In contrast, the reversibility of myeloma cast nephropathy continues to generate much debate, specifically with regard to the efficacy of plasma exchange (PLEX) therapy in treating the condition. A randomized control trial from 2005 found no difference in the outcome of patients with myeloma cast nephropathy, regardless of whether or not they had received PLEX . However, one major criticism of this study is that patients did not receive a renal biopsy. Without tissue confirmation, it is possible that in some patients, renal failure may have been secondary to LCDD or AL, both of which are felt to be irreversible conditions . However, despite the current controversy, many experts continue to recommend PLEX in certain circumstances for myeloma kidney .
In summary, the excess light chains produced in multiple myeloma are the key pathophysiologic factor responsible for renal damage. Light chains crowd the nephron tubules, initiate inflammation, and disrupt brush-border and glomerular function. Hypercalcemia frequently exacerbates the problem. In sum, the kidneys of patients with multiple myeloma are essentially helpless bystanders. Only with aggressive tumor treatment, hydration, radiocontrast material restriction, and—if necessary as a final option—renal transplant, can this damage be minimized.
Dr. Kenny is a chief resident at NYU Langone Medical Center
Peer reviewed by David Goldfarb, MD, Professor of Medicine, Deparment of Medicine (Nephrology), NYU Langone Medical Center and Chief of Nephrology at the Department of Veterans affairs New York Harbor.
Image courtesy of Wikimedia Commons.
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