Multiple Myeloma and Nephropathy (Myeloma Kidney)

Healthful Vitality | 04/12/2019 | By Dr. Faiq Shaikh, MD | Multiple Myeloma and Nephropathy (Myeloma Kidney)

Multiple myeloma (MM) is a cancer of plasma cells, which are a type of blood cells responsible for production of antibodies. It is often subclinical in its early stages. However, in its advanced form it leads to serious complications, especially those involving the musculoskeletal and renal systems.

Approximately 20% of the patients with MM will develop progressive renal failure during the course of the disease. There is a spectrum of renal complications of MM. However, cast nephropathy is a typical renal complication found in myeloma patients, which is caused by free light chains resulting in renal damage. Presence of MM kidney is associated with higher morbidity and mortality in patients with MM. Early deaths in patients with MM are most likely related to infection (45% of cases) and then renal failure (28% of cases).

Presentation

Only 10% of patients with multiple myeloma kidney are found to have nephrotic syndrome. Patients with cast nephropathy tend to have hypercalcemia, severe anemia, advanced myeloma (Durie-Salmon stage 3), and light-chain myeloma. The risk for renal failure correlates with the level of light-chain excretion. Serum creatinine levels (renal function tests) holds prognostic value. If the serum creatinine are <1.4 mg/dl, the median survival has been found to be 3-4 years, compared with 1-2 years for patients with a creatinine of 1.4 to 2.0 mg/dl, and less than 4 months in patients with a creatinine of >2.0.

Pathophysiology

Free light chains are immunoglobulin chains that freely circulating in the serum of patients suffering from multiple myeloma. And they vary greatly based on the physicochemical properties. Some light chains are implicated in Fanconi syndrome, while other forms of light chains form obstructing casts in the distal tubules, which are resistant to proteolysis by trypsin and pepsin (as opposed to Fanconi syndrome). Moreover, some types of light chains not only only accumulate in distal tubules. However, these types tend to self-aggregate into large polymers and create tougher blockades. In the setting of MM, the ability of the proximal tubular cells to reabsorb and catabolize light chains is exceeded, which then reach the distal segment of the nephron and combine with the Tamm–Horsfall mucoprotein (THP) and precipitate forming obstructing casts. This results in the leakage of tubular content into the interstitium, forming casts, which is the hallmark of Myeloma kidney.

In some cases, however, there is evidence of cast nephropathy, without the presence of high serum levels of light chains. Another critical point is that several factors may be implicated in this pathophysiological process. Dehydration may be at the top of this list, especially as precipitated by prescribed diuretics in these patients, which increases the plasma concentration of light chains. Hypercalcaemia is another contributing factor, which may induce vasoconstriction followed by a decrease in GFR. Essential to realizing there is a component of fibrosis in MM kidney, which is explained by the activation of inflammatory cascades leading to tubulointerstitial fibrosis. Tamm-Horsfall proteins and cast formation in the distal tubule can block the glomerular flow, produce tubular atrophy, and contribute to interstitial fibrosis.

Diagnosis for Multiple Myeloma

Early diagnosis and intervention remain key to preventing irreversible renal injuries in patients with multiple myeloma. Evaluation of MM kidney is based on the assessment of renal histology by light microscopy, immunofluorescence and sometimes electron microscopy, which show patterns of tubulointerstitial renal injury occurring in the setting of plasma cell dyscrasias include isolated proximal tubule epithelial cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy. Urine electrophoresis or serum immunoassay can be performed for the identification of monoclonal free light chains.

Management for Multiple Myeloma

Up to half of all patients with multiple myeloma experience some degree of renal insufficiency and in most of these patients, the renal function will improve when managed with fluid rehydration, correction of hypercalcaemia with bisphosphonates, administration of glucocorticoids, or discontinuation of nephrotoxic drugs such as NSAIDs, often within the first 6 weeks. In some cases, even more chronic cases show significant recovery. For more resistant, severe cases, management options include plasma exchange/plasmapheresis, which removes the light chains from the plasma and prevents the development of cast nephropathy.

In addition, some of the novel chemotherapies developed for MM, such as bortezomib and thalidomide can be used without dose reduction in renal impairment. Indeed, in patients with MM kidney, serum free light chain measurements should checked in the first 2 weeks to identify non-responders to antimyeloma therapy, and in whom early change of treatment might be needed to recover from renal damage.

For new patients, the induction therapy comprises dexamethasone alone or in combination with thalidomide or with vincristine, cyclophosphamide, and doxorubicin followed by Autologous stem cell transplant (ASCT), which has had high response rates regardless of Myeloma kidney. Melphalan and Prednisone being reserved for patients who are not eligible for ASCT because of advanced age (>70 to 75 yr) and/or significant comorbidity. 

Prognosis

The outcomes for MM patients with severe acute renal impairment are actually poor, with a median survival of 2 months compared to 3 years with moderate renal impairment. Although the survival rates with acute renal involvement have improved, it was found that only up to 10 months. Indeed, the key to improved survival rates is a rapid reduction in serum levels of the free light chains and the tumor burden. Ultimately, this procedure’s effectiveness depends on the tumor burden, as the risk of renal failure increases as the tumor load increases.

References:

1. Kidney disease and multiple myeloma. Heher EC, Rennke HG, Laubach JP, Richardson PG. Clin J Am Soc Nephrol. 2013 Nov;8(11):2007-17. Available at: https://pubmed.ncbi.nlm.nih.gov/23868898/
2. Multiple Myeloma – Current Status in Diagnostic Testing and Therapy. Kehrer M, Koob S, Strauss A, Wirtz DC, Schmolders J. Z Orthop Unfall 2017 Oct;155(5):575-586. Available at: https://pubmed.ncbi.nlm.nih.gov/28806822/
3. Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. Ecotière L, Thierry A, Debiais-Delpech C. Nephrol Dial Transplant. 2016 Jan;31(1):64-72. Available at: https://pubmed.ncbi.nlm.nih.gov/26289418/
4. Multiple myeloma and kidney disease. Katagiri D, Noiri E, Hinoshita F. ScientificWorldJournal. 2013 Oct 27;2013:487285. doi: 10.1155/2013/487285. eCollection 2013. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826468/

Author:

Faiq Shaikh, M.D., is a dual-fellowship trained Informatician and Imaging physician. He specializes in Imaging Informatics and Oncology research, and has published several scientific papers, abstracts and book chapters. He has several years of experience in academic medicine and biotech-based translational research.

(Also read Artificial Intelligence in Clinical Oncology article by Dr. Faiq Shaikh, MD)