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    • MANUSCRIPT COVER LETTER<br />We are requesting consideration of this paper for publication in the LSMB Newsletter. This paper has not been published previously and is not currently being considered by another journal. We acknowledge any potential conflict of interest. The final version of the manuscript has been read and approved by all of the authors. <br />Dr. Sherri D. Onyiego and Dr. Alan Lebato have been designated as the corresponding author and their mailing addresses are:<br />Dr. Alan Lebato<br /> LSUHSC Family Medicine Residency Program at Lake Charles Memorial Hospital <br />1525 Oak Park Blvd<br /> Lake Charles, LA 70601<br />(337) 494-2023 (Office) <br />(337)434-6750 (Fax)<br />And<br />Dr. Sherri D. Onyiego MD, PhD<br />2221 Hadley St<br />Houston, TX 77003<br /> (832)273-0858 (Cellular)<br />sherridstring@yahoo.com<br />Signatures of all the authors:<br />Dr. Sherri D. Onyiego<br />Dr. Alan L. LeBato<br />Dr. Luan D. Truong<br />Acute Renal Failure as the Initial Presentation of Multiple Myeloma<br />Sherri D. Onyiego, M.D, Ph.D.,……………………….., Luan D. Truong, M.D., …..Alan L. Lebato, M.D.<br />From the Department of Family Medicine, LSUHSC-New Orleans Family Medicine Residency at Lake Charles Memorial Hospital, Lake Charles, LA; <br />And the Department of Pathology, The Methodist Hospital, Houston, TX<br />Please address correspondence to:<br />Alan Lebato, MD<br />From: Department of Family Medicine, LSUHSC-New Orleans Family Medicine Residency at Lake Charles Memorial Hospital, Lake Charles, LA. 1525 Oak Park Blvd, Lake Charles, LA 70601<br />Phone: (337) 494-2023<br />Fax: (337) 494-6750<br />And<br />Sherri D. Onyiego, MD, PhD<br />2221 Hadley St<br />Houston, TX 77003<br />Email: sherridstring@yahoo.com<br />ABSTRACT<br />Multiple myeloma accounts for 1% of all malignancies and slightly more than 10% of all hematological malignancies. Multiple myeloma is characterized by the proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. This proliferation occurs in the bone marrow, resulting in extensive bony destruction and other clinical features including anemia, elevated serum calcium levels and renal insufficiency. This article illustrates a case presentation of a patient who initially presented with renal insuffiency and eventual severe tubulointerstitial injury likely related to myeloma casts. Acute renal failure due to myeloma cast nephropathy is often the initial presentation of multiple myeloma, in which case the diagnosis may be first suggested by the renal biopsy findings and is subsequently confirmed. This sequence is illustrated in the current patient.<br />INTRODUCTARY CASE PRESENTATION<br />A 58-year old Caucasian man was admitted to the hospital from the LSU Family Medicine Clinic of Lake Charles Memorial Hospital for the complaint of nausea, weakness, and dizziness. The patient reported a syncopal episode while doing yard work on the day prior to admission. He felt that it was secondary to the heat and later took a cold shower and rested for the rest of the day. Since the patient’s weakness persisted, he was brought to the Family Medicine clinic for further evaluation. <br />Significant past medical history included an emergency room visit approximately one month previously for a hypertensive crisis. The patient’s antihypertensive regimen was changed in the Emergency Room from lisinopril 20mg daily to lisinopril 40mg daily, with subsequent stabilization of his blood pressure. His current medications included lisinopril, hydrochlorothiazide, allopurinol, and atorvastatin. On admission, laboratory studies showed a serum creatinine of 4.0 mg/dL (normal range 0.5-1.6mg/dL), hemoglobin was 8.8g/dL (normal range 13.0-17.0 gm/dL), and hematocrit was 27% (normal range 37.2-51.9%). A CT scan of the brain on admission in the evaluation of his syncope was normal. One year previously the patient’s baseline creatinine was 1.6 mg/dl likely reflecting underlying hypertension. <br />The admitting diagnoses were acute renal insufficiency, likely secondary to medications and anemia secondary to hypertension-induced chronic renal insufficiency. After rehydration, the patient’s BUN and creatinine improved to 29 mg/dL (normal range 5-26mg/dL) and 2.32 mg/dL (normal range 0.5-1.6mg/dL) respectively; but the hemoglobin remained 8.8g/dL (normal range 13.0-17.0 gm/dL) with normal indices. The patient had no further complaints of nausea and dizziness. His blood pressure remained stable. Upon admission, the patient’s home medications, lisinopril and allopurinol, were discontinued on admission, and amlodipine 2.5mg daily was started for blood pressure control.   After hospital discharge, a 24 hour collection of urine for protein excretion and creatinine clearance was obtained, the study showed a 24-hour urine volume of 3050 ml (normal range 800-1800mL), 24-hour urine protein excretion of 3904 mg/24hr (normal range 0-150 mg/24hr), urine creatinine 2.1gm/24hr (normal range 0.7-2.0 gm/24hr), and a creatinine clearance of 51 cc/min/1.73M2 (normal range 72-141 cc/min/1.73M2). Of note, a 24 hour urine collection taken approximately one year previously during the work up of his renal insufficiency did not reveal any evidence of proteinuria. Two weeks later, the patient returned with complaints of fatigue, but the patient did not have any nausea or anorexia, and his urinary output was normal. However, laboratory studies showed worsening renal insufficiency, with a creatinine of 7.37 mg/dL (normal range 5-26mg/dL), and hemoglobin of 7.8g/dL (normal range 13.0-17.0 gm/dL). He was admitted with a diagnosis of acute renal failure due to rapidly progressive glomerulonephritis or drug-induced acute tubulointerstitial nephritis. After a nephrology consultation was obtained, an ultrasound showed the sizes of the right and left kidneys to be 11.1cm and 12.5cm respectively. Urine analysis revealed 3 red blood cells and 7 white blood cells/ high-power field.  Hemodialysis and epoetin alfa for his anemia were started together after a transfusion of 2 units of packed red blood cells.<br />A renal biopsy was performed and showed severe tubulointerstitial injury possibly related to myeloma cast nephropathy. (See below) <br />A bone marrow biopsy showed active normocellular hematopoietic marrow and trilineage maturation. Serum protein electrophoresis (S-PEP) revealed a monoclonal pattern with abnormality of albumin 3.11 g/dL (normal range 3.40-5.10 g/dL), and normal ranges of α1, α2, β, and γ respectively. However, urine protein electrophoresis (U-PEP) revealed an atypical band or monoclonal spike that was detected in the kappa region, and quantitative Bence Jones protein in a 24 hour urine collection revealed kappa light chains of 150mg/dL (normal range <1.9mg/dL). This was interpreted as a Monoclonal gammopathy with trace IgG and IgA in the urine. There was no evidence of IgM in the urine. Beta-2 microglobulin was elevated at 5.3 mg/L (range 0.5-1.5mg/L). Immunofixation studies revealed the detection of IFE paraprotein. Rheumatoid factor and complement levels were negative and within normal limits respectively. This data did not support any autoimmune involvement. LDH and uric acid were also obtained which were within normal limits. <br />Throughout the rest of his hospitalization the patient’s blood pressure remained stable, and no significant clinical findings were noted aside from edema secondary to steroids, which were switched to a low dose oral taper upon discharge.<br /> The patient was subsequently referred to the MD Anderson Hospital in Houston, TX, where a bone scan revealed a single lytic lesion in the left clavicle. Stem cell transplantation has been recommended for treatment of this patient's multiple myeloma.<br />RENAL BIOPSY FINDINGS<br />Light microscopy: The tissue sections showed 12 glomeruli, three of which were globally sclerotic but the others displayed no significant changes. The blood vessels showed mild intimal fibrosis, consistent with hypertensive changes. The most remarkable changes were severe chronic tubulointerstitial injury characterized by tubular atrophy, interstitial fibrosis, and interstitial inflammatory cell infiltrates (Figure 1A). Several tubules contained casts features characteristic for the types of renal tubular casts seen in multiple myeloma. i.e. large, fragmented, negative by the periodic acid-Schiff stain, and associated with multinucleated giant cells or neutrophils (Figure 1B and 1C).<br />The tissue portion submitted for immunofluoresecent studies for immunoglobulin and complement components showed only medullary tissue, without glomeruli. Tubular casts were not seen and there was no staining for tubular basement membrane.<br />Electron microscopic study showed no significant glomerular changes. Specifically, features of light or heavy chain deposition or amyloidosis were not seen. The final diagnosis was severe tubulointerstitial injury probably related to myeloma casts. <br />DISCUSSION <br />The renal biopsy showed tubulointerstitial injury, which can be correlated with the apparently acute renal failure in this patient. The renal biopsy findings also help establish multiple myeloma as the cause of the acute renal failure. The type of tubular casts seen in this biopsy have characteristic features, i.e. large, fragmented, negative in PAS stain, and associated with multinucleated giant cells, which are almost pathognomonic for multiple myeloma. <br />The monoclonal immunoglobulin fragment, including light or heavy chains, in multiple myeloma can deposit in kidney tissue, and depending mostly on its physicochemical characteristics, can induce myeloma cast nephropathy, light chain or heavy chain deposition disease, light or heavy chain amyloidosis, or crystal nephropathy, among which myeloma cast nephropathy is probably the most frequent. These diseases are usually mutually exclusive in an individual patient, but may co-exist, with the most frequent combination being myeloma cast nephropathy and light chain deposition disease. <br />Patients with multiple myeloma often develop renal failure during the disease course. Its causes may be multifactorial, including, hydroelectrolytic abnormalities, superinfection, radiocontrast nephrotoxicity, medications, and myeloma cast nephropathy. Among these causes, myeloma cast nephropathy is probably the most frequent. Furthermore, acute renal failure due to myeloma cast nephropathy is often the initial presentation of multiple myeloma, in which case the diagnosis may be first suggested by the renal biopsy findings and is subsequently confirmed. This sequence is illustrated in the current patient. <br />Heavy proteinuria is usually the manifestation of significant glomerular injury. Since myeloma cast nephropathy is characterized by marked tubulointerstitial injury, without significant glomerular involvement, protein is usually absent or mild. On the other hand, this patient had nephrotic range proteinuria, which cannot be readily accounted for by myeloma cast nephropathy. As mentioned above, myeloma cast nephropathy can rarely be associated with light chain deposition disease, which tends to involve glomeruli and thus is associated with heavy proteinuria. We therefore carefully evaluate this possible association in the current renal biopsy. Unfortunately, glomeruli are not available in the portion submitted for immunofluorescent study, which is the most sensitive diagnostic test for light chain deposition disease. Electron microscopy often shows typical features of light chain deposition disease, yet it can be negative in the early phases of the disease, thus a negative electron microscopic finding, as in the current case, cannot completely eliminate the possibility of light chain deposition disease. <br />FIGURE LEGEND<br />A: There is tubular atrophy, thickened tubular basement membrane, interstitial fibrosis, and mild interstitial inflammation. Tubular casts, which are large, fragmented, and PAS stain-negative (Arrows), are also seen. The glomeruli are unremarkable (PAS stain x 200). B: The tubular casts are associated with mono and multinucleated macrophages (Arrows) (H&E, x 400). C: Some other tubular casts are associated with neutrophils (Arrows) (H&E, x400). <br />CONCLUSIONS<br />Multiple myeloma accounts for 1% of all malignancies and slightly more than 10% of all hematological malignancies. Annual incidence of the disease ranges from 4 to 5 per 100,000. Multiple myeloma occurs in all races and geographic locations. The incidence in African Americans is twice that of Caucasians and it is slightly more frequent in men than women.<br />Multiple myeloma is characterized by the proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. This proliferation occurs in the bone marrow and results in extensive bony destruction with osteolytic lesions, osteopenia, pathologic fractures and pain. Other clinical features may include anemia, elevated serum calcium levels and renal insufficiency. <br />Bone pain, particularly in the chest and back, is the most common presenting complaint. The bone pain is more common with movement and usually does not awaken the patient from sleep except with movement. Bone pain occurs in roughly 60% of patients. Weakness and fatigue may also be noted in up to 32% of patients and is felt to be associated with anemia. Weight loss may occur in up to 24% of patients. Fever is uncommon (<1%) unless associated with co-existing infection. Conventional radiographs will reveal a lesion in 80% of patients at the time of diagnosis. Focal, lytic lesions will be found in 60% of these patients with osteoporosis, pathologic fractures, or compression fractures being present in 20% of the patients. Hypercalcemia is present in 20% of patients.<br />The literature supports the fact that renal insufficiency ranging from mild to severe cases can be found in as many as 50% of patients with multiple myeloma. This renal impairment usually presents as proteinuria and renal insufficiency. The pathogenesis can often be multifactorial. Light chain immunoglobulin, in particular, can directly cause kidney destruction by causing proximal tubular damage and myeloma cast nephropathy. (2) Dehydration, nephrotoxic drugs (ex, NSAIDs, and certain antibiotics), infection, hyperuricemia, and hypercalcemia are other factors that may contribute to renal insufficiency in myeloma patients, and should consequently be managed in the context of the clinical presentation. The risk for the development and severity of renal failure has been associated with the level of light chain excretion. ( 1,3 ) When comparing patients with multiple myeloma without renal failure versus multiple myeloma patients who present with renal failure/insufficiency or cast nephropathy, the patients with concomitant renal insufficiency are more likely to have concomitant hypercalcemia, severe anemia, and advanced myeloma, in particular light chain myeloma. ( 1)<br />This patient was unusual in that he had no bone pain, a normal bone marrow, and normal serum calcium levels on initial workup. Radiographic studies found only a single lytic lesion in his clavicle, and that was after the diagnosis was made by electrophoresis and only after it was suspected by renal biopsy. <br />Early and aggressive treatment and management of the renal insufficiency and myeloma are critical for improving survival. One of the mainstays of treatment is to decrease the level of light chain production by chemotherapeutic agents alone or in combination with stem cell transplantation, both of which have been offered to the patient presented in this case.<br />ACKNOWLEDGEMENTS<br />The authors are grateful for the consultation and advice: Dr. Luan Truong, Dr. Michael Broussard, and Dr. Tony Leung.<br />REFERENCES<br />Korbet S.M., Schwartz M.M. Multiple Myeloma. J Am Soc Nephrol 17: 2533-2545, 2006<br />Samson D. et al. Diagnosis and Management of Multiple Myeloma. Guideline. British Journal of Haematology. 2001, 115, 522-540<br />Knudsen LM, et al. Renal function in newly diagnosed multiple myeloma: A demographic study of 1353 patients. The Nordic Myeloma Study Group. Eur J Haematol 65: 175-181, 2000.<br />