Multiple myeloma (MM) is a plasma cell disorder characterized by clonal proliferation of malignant plasma cells producing monoclonal proteins and causing organ damage. The involvement of kidney in MM and other plasma cell dyscrasias is very common. At the time of presentation, about 50% of the patients could have involvement of the kidney, and it is associated with higher mortality.
Most common renal injury is immunoglobulin (Ig) mediated. This includes cast nephropathy (also known as myeloma kidney), monoclonal immunoglobulin deposition disease (MIDD), and light chain amyloidosis (AL). IgA-independent mechanisms include hypercalcemia, volume depletion, sepsis, tumor lysis and medication toxicity. GN can present as membranoproliferative or crescentic, or cryoglobulinemia is observed. Occasionally minimal change disease can also be seen. In cast nephropathy, the filtered monoclonal light chains can cause cast formation, thus obstructing the distal tubules. Depending on the amount of the light chains, tubular rupture is also seen in severe cases. Thickening of the basement membranes of the glomerulus and the tubules is seen in MIDD due to deposition of the filtered immunoglobulin. Interaction among the immunoglobulin light chains and other proteins results in beta-pleated sheets thus causing AL. Thrombotic microangiopathy (TMA) can result from immunoglobulin-mediated endothelial damage or with the use of chemotherapy. Deposition of monoclonal IgM (larger size when compared to IgG) can result in hyperviscosity syndrome. Likewise, deposition of monoclonal IgA can result in Henoch-Schonlein purpura (HSP) or IgA nephropathy.
Kidney involvement can also be seen in patients with monoclonal gammopathy of undetermined significance (MGUS) and is called monoclonal gammopathy of renal significance (MGRS).
MM can affect any race, but it is twice as common in African Americans, predominant in men, and the median age is about 65 to 70 years. The annual incidence in the United States is about 5.6 cases per 100,000. In the United States, it accounts for about 1% of all the cancers and about 17% of all the hematological malignancies. About 80% of the patients with MM have chromosomal abnormalities, and the remaining have genetic abnormalities.
Kidney involvement has been well documented in patients with plasma cell disorders. The light chains produced are filtered through the glomerulus and are endocytosed by the megalin receptors. Few of these light chains are resistant to degradation and tend to accumulate causing damage to the proximal tubules. It can also cause Fanconi syndrome by the formation of crystalline inclusions in the proximal tubules. The involvement of kidney in MM can be due to various mechanisms such as immunoglobulin-dependent, Ig-independent, glomerulonephritis (GN), and direct parenchymal invasion by the plasma cells.
Initial symptoms may be vague including loss of appetite and weight, bone pain, or symptoms related to renal failure. Laboratory workup may reveal abnormal kidney function or worsening chronic kidney disease (CKD), hypercalcemia and anemia. Patients with light chain cast nephropathy have acute kidney injury (AKI) or worsening CKD and proteinuria. The proteinuria is predominantly monoclonal immunoglobulin known as Bence Jones protein. Patients with AL and MIDD can have systemic symptoms that include purpura, gastrointestinal bleeding, the involvement of the heart resulting in arrhythmias, or symptoms related to heart failure. The cardiac involvement is more common in AL. Typically hypertension is seen in patients with cast nephropathy and MIDD due to renal failure. Patients with AL can have hypotension due to cardiac involvement, and they have albuminuria.
Urine dipstick is misleading as it cannot detect the paraproteins. It only detects albumin. The urine needs to be tested with sulfosalicylic acid to detect the abnormal myeloma proteins. Quantification of the 24-hour urine protein would be abnormal due to the presence of paraproteins. Paraproteins should be suspected when the ratio of urine microalbumin over urine creatinine is low and the ratio of urine protein over urine creatinine is high. Serum free light chains (SFLC), serum electrophoresis, urine electrophoresis and immunofixation should be performed.
The SFLC assay quantitates the concentration of circulating kappa and lambda (unbound) free light chains (FLCs). The normal serum free kappa to lambda ratio is 0.26 to 1.65 in patients without kidney impairment. Patients with kidney impairment have high SFLC, and it can be as high as 3.1 in patients with severe kidney impairment. Elevated FLCs along with an abnormal kappa to lambda ratio indicates a monoclonal plasma cell disorder. The SFLC assay is more sensitive than the urine protein electrophoresis for detecting FLCs. Light chain cast nephropathy should be strongly suspected in any patient presenting with unexplained kidney injury over a period of fewer than 6 months and an elevated FLC level of greater than or equal to 1500 mg/L.
Though kidney biopsy is the diagnostic test to confirm the association between a monoclonal protein and kidney disease, it can be deferred in the following situations:
Initial treatment should be focused on assessing the degree of renal impairment and correcting the hemodynamics, volume status, and electrolyte disturbances. Formation of casts and paraprotein concentration need to be minimized. Nephrotoxic agents including non-steroidal anti-inflammatory agents, renin-angiotensin inhibitors, intravenous contrast, and hypotension need to be avoided. Patients need to be adequately hydrated. Loop diuretics should be avoided, as they can precipitate cast formation. Depending on the severity of the renal impairment and the symptoms, hemodialysis is needed to correct acid-base balance, electrolyte disturbances, volume overload symptoms and uremic symptoms.
The concentration of the paraproteins can be decreased by the use of chemotherapy and plasma exchange or plasmapheresis. Plasmapheresis is considered in patients with cast nephropathy to reduce the concentration of the paraproteins, but its efficacy has not been well established. It does not have any effect on overall survival or need for hemodialysis. Patients with hyperviscosity syndrome do benefit with plasmapheresis.
About 80% of the patients could have a recovery of renal function by 3 weeks if there is a reduction in the SFLC by at least 60%. This can be achieved by early diagnosis and prompt initiation of treatment. The most commonly used agent is bortezomib, and it has a rapid onset of action. It is not renally dosed, however, the dosing of lenalidomide needs to be adjusted based on the creatinine clearance.
During treatment, labs need to be monitored carefully for any evidence of tumor lysis syndrome which is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. A kidney transplant can be considered if the myeloma is in remission for at least 3 to 5 years. It can be associated with recurrence of myeloma due to the use of immunosuppressive agents and Ig-mediated graft rejection.
The prognosis depends mainly on the extent of the kidney injury. Patients who have kidney dysfunction could have an average survival of about 20 months. Response to chemotherapy is the main predictor of the survival outcomes. Patients who respond to the chemotherapy have an average survival of 3 years.
Multiple myeloma affects many organs systems and is best managed by an interprofessional team. Kidney involvement has been well documented in patients with plasma cell disorders. The light chains produced are filtered through the glomerulus and are endocytosed by the megalin receptors. Few of these light chains are resistant to degradation and tend to accumulate causing damage to the proximal tubules. It can also cause Fanconi syndrome by the formation of crystalline inclusions in the proximal tubules. It is important to get the nephrologist involved early in the course of the disorder as renal failure is a complication of multiple myeloma. Initial treatment should be focused on assessing the degree of renal impairment, correcting the hemodynamics, volume status and electrolyte disturbances. The hematologist should be consulted on the overall management of the disorder. the prognosis for patients with renal involvement in multiple myeloma depends on the severity of the renal dysfunction and other comorbidities. For those whose renal function is irreversibly damaged, dialysis is necessary. However, at this stage the life expectancy is significantly reduced. (Level II)
|||Gödecke V,Schmidt JJ,Bräsen JH,Koenecke C,Haller H, [Diagnosis and treatment of kidney involvement in plasma cell diseases : Renal involvement in multiple myeloma and monoclonal gammopathies]. Der Internist. 2019 Jan 11; [PubMed PMID: 30635666]|
|||Boudhabhay I,Titah C,Talbot A,Harel S,Verine J,Touchard G,Kaaki S,Gabison E,Vasseur V,Mauget-Faÿsse M,Sené T, Multiple myeloma with crystal-storing histiocytosis, crystalline podocytopathy, and light chain proximal tubulopathy, revealed by retinal abnormalities: A case report. Medicine. 2018 Dec; [PubMed PMID: 30593133]|
|||Daidola G,Guarena C,Brustia M,Leonardi G,Vigotti FN,Marciello A,Bianco S,Chiarinotti D,Saltarelli M,Besso L,Biancone L, [Efficacy of SUPRA HFR in the treatment of acute renal damage during multiple myeloma]. Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. 2018 Dec; [PubMed PMID: 30550040]|
|||Favà A,Fulladosa X,Montero N,Draibe J,Torras J,Gomà M,Cruzado JM, Treatment of multiple myeloma with renal involvement: the nephrologist's view. Clinical kidney journal. 2018 Dec; [PubMed PMID: 30524711]|
|||Burwick N,Adams SV,Todd-Stenberg JA,Burrows NR,Pavkov ME,O'Hare AM, Association of Monoclonal Gammopathy with Progression to ESKD among US Veterans. Clinical journal of the American Society of Nephrology : CJASN. 2018 Dec 7; [PubMed PMID: 30442867]|
|||Kitchlu A,McArthur E,Amir E,Booth CM,Sutradhar R,Majeed H,Nash DM,Silver SA,Garg AX,Chan CT,Kim SJ,Wald R, Acute Kidney Injury in Patients Receiving Systemic Treatment for Cancer: A Population-Based Cohort Study. Journal of the National Cancer Institute. 2018 Nov 13; [PubMed PMID: 30423160]|
|||Takano J,Mine S,Mochizuki M,Tanaka N,Hagiwara S, Late-stage myeloma invades kidney without significant effect on renal function: findings from 53 autopsies in a single institute. International journal of hematology. 2018 Oct 16; [PubMed PMID: 30327925]|
|||Huskey JL,Heilman RL,Khamash H,Fonseca R, Kidney Transplant in the Era of Modern Therapy for Multiple Myeloma. Transplantation. 2018 Dec; [PubMed PMID: 30211830]|
|||[Expert consensus for the diagnosis and treatment of patients with renal impairment of multiple myeloma]. Zhonghua nei ke za zhi. 2017 Nov 1; [PubMed PMID: 29136724]|
|||[The guidelines for the diagnosis and management of multiple myeloma in China (2017 revision)]. Zhonghua nei ke za zhi. 2017 Nov 1; [PubMed PMID: 29136723]|