Primary renal lymphoma (PRL) is a rare

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1 KIDNEY BIOPSY TEACHING CASE Acute Renal Failure Due to a Primary Renal B-Cell Lymphoma Charles J. Diskin, MD, 1 Thomas J. Stokes, MD, 1 Linda M. Dansby, MD, 1 Lautrec Radcliff, MD, 1 Thomas B. Carter, DO, 1 Edith Graves, MD, 1 Deborah Byron, MD, 2 and William J. Cook, MD, PhD 3 INDEX WORDS: Acute renal failure; large B-cell non-hodgkin lymphoma; renal biopsy; rituximab. Primary renal lymphoma (PRL) is a rare entity in which lymphoma originates in the renal parenchyma and does not represent involvement of the kidney from extrarenal disease. 1 PRL presenting as acute renal failure is an even rarer entity. Because there are few cases, optimal therapy is unknown; however, generally poor renal function recovery rates and poor patient survival were reported. We report a patient who presented with acute renal failure caused by PRL with a favorable response to chemotherapy with rituximab in addition to previously reported therapy. CASE REPORT Clinical History A 77-year-old retired physician with a serum creatinine level of 1.0 mg/dl (88.4 mol/l) underwent lumbosacral surgery at another institution. Three months after surgery, he was noted to have anorexia, a 20-pound weight loss, and a serum creatinine level of 4.5 mg/dl (398 mol/l) that increased to 9.8 mg/dl (866 mol/l) within 1 week. Ultrasonography showed his kidneys to be large (left, 13.5 cm; right, 12.5 cm) with no obstruction. The patient had no history of sicca syndrome or Sjögren disease. Because his doctors believed the anorexia and weight loss were caused by renal failure, he started dialysis therapy and then was discharged to a nursing facility. Because of continued anorexia and weakness, he was transferred to our hospital for additional examination and treatment. Physical examination on admission showed blood pressure of 154/86 mm Hg, but otherwise normal vital signs. No lymphadenopathy or edema was identified, and no abnormality was noted on physical examination other than the healed lumbosacral scar. Admission laboratory studies showed the following values: hemoglobin, 11.6 g/dl (116 g/l); leukocytes, 7,600/ L; serum creatinine, 7.3 mg/dl (645 mol/l); normal electrolytes with corrected serum calcium of 9.3 mg/dl (2.32 mmol/l); uric acid, 2.6 mg/dl (155 mol/l); and potassium, 5.3 meq/l (mmol/l). A 24-hour urine measurement showed creatinine clearance of 3 ml/min (0.05 ml/s) and 880 mg of protein. Although serum protein electrophoresis showed a slight increase in -globulin level at 1.8 g/dl (18 g/l), no abnormal protein level was found. Sedimentation rate was 31 mm/h with a C-reactive protein level of 8.2 mg/dl. All test results for antinuclear, anti- DNA, anti glomerular basement membrane, and antineutrophil cytoplasmic antibodies were negative, with normal complement and angiotensin-converting enzyme levels. Percutaneous biopsy of the right kidney guided by computed tomography was performed. Kidney Biopsy Light microscopic evaluation showed 2 cores of renal medulla and 2 cores of cortex with 7 glomeruli. There was moderately increased mesangial matrix with no proliferation; capillary basement membranes were unremarkable with silver stain. There was dense lymphocytic infiltration throughout the cortex (Fig 1A) and focally in the medulla, consistent with PRL. Tumor cells were large with atypical nuclear features, and numerous mitoses were noted (Fig 1B). Periodic acid-schiff hematoxylin and trichrome stains showed tubular atrophy with no tubulitis. An immunohistochemical stain for CD20 was strongly positive in most neoplastic cells throughout the cortex and focally in the medulla (Fig 2A). Staining for CD3 showed only occasional cells with positive staining (Fig 2B). Immunofluorescence sections contained 3 glomeruli. There was diffuse 1 mesangial staining for C3, but stains for immunoglobulin G, immunoglobulin M, immunoglobulin A, C1q, and light chains were negative. There was 2 staining for C3 in vessels and focally in tubular basement membranes. Ultrastructural examination confirmed marked expansion of the interstitium by tumor cells. Nuclei were irregularly shaped with dispersed chromatin and 1 or more small nucleoli. There were relatively few organelles; scattered mitochondria and rare lysosomes were noted. No intercellular junctions were identified. Diagnosis The final diagnosis was poorly differentiated large B-cell lymphoma. From the 1 Hypertension, Nephrology, Dialysis and Transplantation Clinic, Auburn University, Auburn; 2 Internal Medicine Clinic, Opelika; and 3 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL. Received March 13, Accepted in revised form August 7, Originally published online as doi: /j.ajkd on October 3, Address correspondence to Charles J. Diskin, MD, Hypertension, Nephrology, Dialysis & Transplantation, Bldg 21, 121 North 20th St, Opelika, AL hndt512@bellsouth.net 2007 by the National Kidney Foundation, Inc /07/ $32.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 50, No 5 (November), 2007: pp

2 886 Diskin et al Figure 1. Diffuse dense lymphomatous infiltration in the cortex (hematoxylin and eosin; original magnification [A] 40; [B] 200). Clinical Follow-Up The patient underwent an extensive search for extrarenal lymphoma. Additional computed tomography of the chest, head, abdomen, and pelvis showed a 2-cm mass in the right kidney that was believed to be a more localized area of the lymphoma (Fig 3), with no evidence of hematoma from the biopsy. However, no lymphadenopathy or other organ involvement was identified. The diagnosis was PRL with no extrarenal involvement. The patient began treatment with cyclophosphamide (1,000 mg intravenously), vincristine (2 mg intravenously), prednisone (80 mg/d for 5 days), and rituximab (675 mg intravenously). Within 1 week, urine output improved, with a serum creatinine level of only 2.6 mg/dl (230 mol/l) and an estimated glomerular filtration rate by means of the Modification of Diet in Renal Disease Study equation of 26 ml/min/1.73 m 2 (0.43 ml/s/1.73 m 2 ). Six months after initiation of chemotherapy, he remained free of dialysis therapy, had a serum creatinine level of 2.4 mg/dl (212 mol/l), gained 15 pounds, and was considered to be in remission. DISCUSSION PRL as a clinical entity has been disputed because the kidneys do not contain lymphatic tissue and the mechanism of development of PRL is unclear. 2,3 The diagnosis should be made only in the absence of extrarenal lymphoma, paraproteinemia, and leukemic blood phase. 4 Most of the few reported cases showed rapid

3 Treatment of Primary Renal Lymphoma With Rituximab 887 Figure 2. Immunochemical stains for (A) CD20 and (B) CD3 (anti-cd20; original magnification 200). progression and a poor prognosis, with a 1-year mortality rate of 75%. 5 Histologically, most cases showed a diffuse pattern of proliferation, with B-cell type shown on immunohistochemistry. 4 Etiologic factors for PRL are unknown. Several decades ago, low-grade B-cell lymphomas of mucosa-associated lymphoid tissue were shown to arise in nonlymphoid tissue because of chronic inflammation However, renal mucosa-associated lymphoid tissue is uncommon. 11,12 Although 1 case of an immunoblastic lymphoma with human immunodeficiency virus infection 13 and 1 case of the African form of Burkitt lymphoma 14 were reported as PRL, there is no evidence that chronic inflammation usually induces PRL. All attempts to find a linkage of PRL to such chronic inflammation as chronic pyelonephritis, 1 Sjögren syndrome, 1 systemic lupus erythematosus, 1 or Epstein-Barr virus have failed. 3

4 888 Diskin et al Figure 3. Computed tomographic scan of the abdomen shows no lymphadenopathy, but a 2-cm mass (white line) in the right kidney believed to be a more localized form of the diffuse lymphomatous involvement. Acute renal failure caused by PRL is extremely rare. As of 2004, only 11 patients with PRL presenting as acute renal failure were reported, 15 and since then, only 2 additional patients were reported, 14,16 whereas 7 other patients with ARF caused by lymphomatous infiltration either had extrarenal lymphoma 14,17-19 or leukemia 18 and thus did not meet criteria for PRL. In our patient, we found no cause other than PRL for impaired renal function. Pathophysiological characteristics of acute renal failure in patients with PRL are believed to be caused by tubular compression and impairment of renal parenchymal blood flow, 2 which might be expected from the massive lymphocytic infiltration noted in our patient. The rapid improvement in renal function that our patient experienced after treatment of his lymphoma suggests that PRL was the cause of his dysfunction. Because involvement of 1 kidney should not have resulted in renal failure, our patient most likely had bilateral involvement, although the biopsy was only from the right kidney. There is no standard treatment for patients with PRL because the number of reported cases remains small. Although the most common treatment is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), 1,2,15,18,20 various other chemotherapeutic agents were tried. 5,15,16,20 However, to our knowledge, this is the first time rituximab has been added. Rituximab is a chimeric monoclonal antibody against CD20, which is a surface antigen on both normal and neoplastic B lymphocytes. Although it was not previously used in patients with PRL, in those with other B-cell lymphomas, the addition of rituximab was associated with significantly better complete response and overall survival. 21 Although survival in patients with untreated PRL is often days, with no recovery of renal function, 15 chemotherapy has increased survival. One patient was able to experience a remission after chemotherapy and nephrectomy, 2 whereas another recovered renal function within a month of treatment with CHOP. 16 It is difficult to make generalizations; however, the course of our patient suggests that rituximab might be a useful addition to the chemotherapeutic regimen. ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None. REFERENCES 1. Brouland JP, Meeus F, Rossert J, et al: Primary bilateral B-cell renal lymphoma: A case report and review of the literature. Am J Kidney Dis 24: , 1994

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