Multiple myeloma presenting as acute renal failure

Multiple myeloma is a plasma cell dyscrasia that can have various clinical presentations. Signs and symptoms often reflect plasma cell infiltration into organs but can be subtle. We report a case of a woman who presented with nonoliguric acute kidney injury as the initial manifestation of multiple myeloma.

CASE PRESENTATION

A 68-year-old African American woman presented to the emergency department after routine blood work with her primary care physician revealed abnormal renal function studies. Six months prior to admission, she began to have nonspecific pain in her back, knees, and feet. Degenerative osteoarthritis was diagnosed, and she was treated with conservative measures including physical therapy and occasional use of nonsteroidal antiinflammatory medicines. However, the pain persisted, especially in her right knee, and she had to ambulate with a cane. One week prior to admission, the patient developed abdominal cramps with nausea, vomiting, and decreased appetite. She saw her physician and had blood work done, which showed marked elevation of blood urea nitrogen and creatinine concentrations. She reported subjective low-grade fevers, but denied any weight loss, chills, or night sweats. She also denied any dysuria, gross hematuria, or any decrease in urine output.

Her past medical history included long-standing hypertension and mild obesity. Her home medications included benazepril and hydrochlorothiazide for blood pressure and nabumetone and other over-the-counter antiinflammatory medications for joint pain. The patient also tried various health food supplements, including bromelain, ginger root, and CuraMed antioxidant, about 1 month prior to admission to help with her pain. She denied any smoking, drinking, or illicit drug use and was a retired schoolteacher.

The patient was comfortable in the emergency department with normal vital signs, and physical examination revealed some mild discomfort to deep palpation in her abdomen. There was no erythema, effusion, or warmth around her knees, but the patient did have mild tenderness to palpation around her right knee. There was no evidence of neuropathy. Her pertinent initial laboratory values included a blood urea nitrogen concentration of 103 mg/dL, a serum creatinine level of 15.0 mg/dL, an albumin level of 3.4 g/dL, and a mildly elevated globulin level of 4.0 g/dL. The patient had a hemoglobin of 13.5 g/dL and hematocrit of 38% with no rouleaux seen on peripheral smear. The serum calcium level and total protein were within normal limits. A dipstick urinalysis with microscopic examination showed 1+ protein, 1+ blood, and 5 to 10 granular casts.

The patient was admitted for her acute kidney failure. A 24-hour urine collection, with a collected volume of 2.4 L, contained 2.6 g of protein and 1.1 g of creatinine. A renal sonogram on admission was unremarkable. The patient's creatinine continued to trend up the first few days of admission despite receiving intravenous fluids and holding potentially nephrotoxic agents. Since the etiology of the patient's renal failure at this point was still unclear, a percutaneous renal biopsy was performed. On light microscopy, there was evidence of large eosinophilic hyaline casts with mononuclear cells and multinucleated giant cells, and immunofluorescent microscopy showed positive kappa staining of tubular casts; these findings were consistent with myeloma cast nephropathy (Figure 1). No amyloid was present on the biopsy.

Figure 1.

Renal biopsy specimens from our patient showing characteristic myeloma cast nephropathy. The tubules have large eosinophilic hyaline casts with surrounding mononuclear cells, multinucleated giant cells, and neutrophils.

Over the next few days, laboratory tests ordered on admission became available. The patient's serum protein electrophoresis identified a monoclonal spike in the gamma region, and the serum immunofixation electrophoresis confirmed it as a monoclonal free kappa band in the gamma region. Urine protein electrophoresis showed an M-spike of 61.9 mg/dL. A radiographic skeletal survey showed scattered lytic lesions in the proximal right humerus, right scapula, and the distal femurs bilaterally (Figure 2). Multiple osteosclerotic lesions were also seen in the skull (Figure 3).

Figure 2.

Lytic lesions in bilateral femurs.

Figure 3.

Osteosclerotic lesions in the skull.

At this point, hematology was consulted, and a bone marrow aspirate and core biopsy revealed hypercellularity and diffuse plasmacytosis of up to 60% plasma cells (Figure 4). Flow cytometry of the biopsy confirmed a monoclonal plasma population with kappa restriction, and ancillary stains for amyloid were negative. A myeloma fluorescent in situ hybridization panel on the bone marrow indicated a t(11;14)(q13;q32) translocation. Further laboratory results revealed that the patient had an elevated serum free kappa light chain at 1080 mg/dL with a kappa/lambda ratio of 800. The beta-2 microglobulin level was also elevated at 15.4 mg/L.

Figure 4.

High-magnification (40×) view of bone marrow biopsy showing plasmacytosis.

The patient was diagnosed with free light chain multiple myeloma with cast nephropathy. Chemotherapy was initiated in the hospital with two cycles of bortezomib infusions, one every 72 hours for four doses, along with dexamethasone. The patient had an excellent response to chemotherapy, as her serum creatinine began to improve and she never required renal replacement therapy. The patient received one dose of pamidronate in the hospital, and at the time of discharge, her serum creatinine stabilized around 2.0 mg/dL. She was scheduled to follow up with hematology as an outpatient to receive more chemotherapy with bortezomib and dexamethasone.

DISCUSSION

Multiple myeloma is a malignant proliferation of plasma cells resulting in a monoclonal immunoglobulin production. The plasma cells proliferate in the bone marrow, resulting in skeletal destruction. Multiple myeloma accounts for about 10% of hematologic malignancies in the United States, with an annual incidence of 4 to 5 per 100,000. African Americans have a two to three time greater incidence than Caucasians, and there is a slight predilection for men over women. It is a disease of older adults, with a median age of diagnosis around 66 years old (1–3).

Presenting symptoms are variable, including fatigue, generalized weakness, weight loss, and bone pain, and there is often evidence of some organ damage. Radiculopathy can be present if there is nerve compression from an extramedullary plasmacytoma or any bone fragments from a vertebral fracture. Basic laboratory values frequently reflect an anemia, elevated serum creatinine, or hypercalcemia (4). Anemia is the most common finding in patients who are diagnosed with multiple myeloma, but our patient did not present with anemia. She also did not have hypercalcemia despite numerous destructive bone lesions. The lack of these two findings in our patient made it a rare presentation of multiple myeloma. A serum protein electrophoresis can identify a monoclonal (M) protein, and a serum immunofixation confirms the presence and the type of immunoglobulin. A subtype of myeloma is light chain myeloma, where only immunoglobulin light chains are expressed, and a serum free monoclonal light chain analysis can quantify the exact amount. Cast nephropathy is more common in light chain myeloma. The ratio of kappa to lambda light chains is a strong clue to diagnosis, since both the kappa and lambda light chains accumulate with renal insufficiency.

The pathophysiology of renal failure in multiple myeloma is often multifactorial but is mostly due to the high excretion of immunoglobulin free light chains. When the light chains combine with Tamm-Horsfall proteins, they form obstructing casts (5). Chemotherapy should therefore be initiated rapidly to decrease light chain production. Intravenous fluids can be given to treat volume depletion, hypercalcemia, or hyperuricemia. Plasmapheresis can also be instituted to remove free light chains if needed, but despite various studies, its exact benefits are still unclear (6, 7). Dialysis using a high flux dialyzer is another method to remove free light chains but is less effective than plasmapheresis and the evidence is even less convincing. Renal replacement therapy should therefore be initiated only for the usual indications in renal failure (8).

On laboratory results, a urinalysis dipstick examination may be unremarkable since it detects mostly albumin. The proteinuria in cast nephropathy is mostly monoclonal protein or Bence Jones proteinuria. In this situation, a 24-hour urine collection is more useful to quantify the exact amount of protein. On peripheral blood smear, there can be rouleaux formation, leukopenia, or thrombocytopenia. Rouleaux formation occurs when red blood cells stack upon each other as a result of elevated serum globulins. Bone marrow aspirate and biopsy will show a predominance of clonal plasma cells (3).

A radiological skeletal survey is used to identify bone involvement. Standard views look at the chest, spine, humerus, femur, pelvis, and skull. Traditional findings include lytic lesions, osteopenia, or fractures. Osteosclerotic lesions are rare but can occur, as in our patient (9).

The International Myeloma Working Group and the Mayo Clinic have suggested diagnostic criteria for multiple myeloma. The three criteria include the presence of a serum or urinary monoclonal protein, presence of clonal plasma cells in the bone marrow (generally 10% or more plasma cells), and end organ damage or tissue impairment related to the plasma cell dyscrasia such as hypercalcemia, renal failure, anemia, or lytic bone lesions (10, 11).

There are two staging systems for myeloma, the international staging system and the Durie-Salmon staging system. The international staging system looks at the beta-2 microglobulin level and the serum albumin and is used for patients with symptomatic myeloma. It is simpler and more objective. The serum beta-2 microglobulin level is a prognostic indicator, as higher levels are associated with greater tumor burden, renal failure, and lower survival rates (12, 13). The Durie-Salmon system is more complex and incorporates various factors such as tumor cell density, indicators of end organ damage, and immunoglobulin levels (14).

The serum free light chain ratio also has some prognostic value in patients with symptomatic myeloma. It is the ratio of kappa/lambda concentrations and acts as a surrogate marker for clonal expansion. A large referral center trial done at the Mayo Clinic found that patients with a ratio of <0.03 or >32 had shorter median survival compared to those with a ratio between 0.03 and 32 (15). Certain translocations have also been associated with a poor prognosis: t(4;14), t(14;16), and del17p13. The median survival with these translocations is about 25 months (16).

The general approach to treatment of patients with myeloma involves chemotherapy and autologous hematopoietic cell transplantation (HCT). The first step is to stratify the patient as high risk or standard risk. Generally, high-risk patients are those with the above-mentioned translocations, and patients without the translocations are considered standard risk (17). The next step is to determine eligibility for HCT; the determination is based on both objective laboratory values and the risk-benefit assessment for the patient.

Many clinical trials have evaluated chemotherapy regimens for patients who are at high or standard risk and eligible or ineligible for HCT. Usual classes of chemotherapy medications include melphalan, a nitrogen mustard alkylating agent, thalidomide and its analogues, a novel proteasome inhibitor bortezomib, and steroids. Patients who are not eligible for HCT are usually treated with combinations of melphalan and prednisone with or without bortezomib or thalidomide and its analogues (18, 19).

For patients eligible for HCT, traditional induction chemotherapy regimens include lenalidomide with dexamethasone. Various clinical trials have looked at concomitant high- or low-dose dexamethasone administration. Recent studies have suggested higher mortality rates with high-dose administration in combination with a thalidomide (20, 21). Bortezomib regimens have also been useful in patients with renal failure, which is applicable to our patient.

Dimopoulos et al (22) summarized various clinical trials involving bortezomib-based regimens, as this medication has been proven effective and safe for patients with renal insufficiency. Some studies even resulted in improvement in renal function. The authors recommended bortezomib and high-dose dexamethasone therapy for patients with myeloma and any grade of renal insufficiency.

Bisphosphonates are also appropriate in the management of patients with multiple myeloma, specifically those with lytic bone lesions. For patients without lytic lesions, it can still be helpful if the patient has osteopenia or osteoporosis. The bisphosphonates help prevent development of new lytic lesions (23). Both intravenous pamidronate and zoledronic acid have been demonstrated to reduce skeletal-related events in patients with multiple myeloma (24, 25). For patients with renal insufficiency, the use of bisphosphonates can be controversial, as they tend to have very long half lives. Therefore, renal function should be monitored closely in patients receiving bisphosphonate therapy.

Acknowledgments

Special thanks to Nesrin Onur, MD, and Stacy Hinson, MD, from the Department of Pathology for providing pathology images.