Concurrent nephrotic syndrome and acute renal failure caused by chronic lymphocytic leukemia (CLL): a case report and literature review

A 54-year-old male Chinese patient was admitted to the Shunde People's hospital on March 7, 2008, complaining of nocturia and edema of face and both lower extremities for more than two months. The patient had no history of any renal disease. Physical examinations revealed normal vital signs, moderate hypertension (162/96 mmHg) and pitting edema of the lower extremities. Enlargement of lymph nodes involving inguinal, axillary, submaxillary and supraclavicular fossa with a diameter of more than 1 cm was found. The remainder of the examination was unremarkable.

Both his hemoglobin and erythrocyte count were in normal range. The leukocytes increased to 16.8 × 10⁹/L with elevated lymphocytic proportion by 61.8% (normal range: 24%-40%). Urine analysis showed proteinuria of 5 g/L with a RBC count of 150/μL. His 24-hour total urinary protein excretion was 5.11 g and serum albumin level was 38 g/L. The blood creatinine (Cr) concentration was 290.04 μmol/L (normal range: 53-115 umol/l) and the urea nitrogen (BUN) was 13.49 mmol/L (normal range: 2.9-8.6 mmol/l) indicating the impaired renal function. Both Ig-M (kappa) monoclonal protein and free kappa were detected in his serum by immunofixation electrophoresis, but urine Bence Jones protein was negative. He also had high serum IgM concentration (3.9 g/L, normal range: 0.50-2.20 g/L) while the IgG and IgA levels were normal. The serum complement 3 decreased to 0.03 g/L (normal range: 0.79-1.17 g/l). The tests for antinuclear antibody, rheumatoid factor, cryoglobulin and hepatitis virus B and C all showed negative. The bone marrow aspiration showed increased cellularity and the accumulation of small immature-appearing lymphocytes, without increase of plasma cells. Flow cytometric analysis showed that those lymphocytes were positive for CD5, CD19, CD20, HLA-DR, kappa and surface membrane IgM, and negative for CD3, CD7, CD10, CD38 and lambda (Figure 1). The CT scanning revealed numerous intumesced lymph nodes in the neck, thoracic cavity, celiac and retroperitoneal space (Figure 2). Liver and spleen were both enlarged with dense and fine sonogram. The echocardiography indicated mildly and symmetrically thickened left ventricular wall. The patient was diagnosed with acute renal failure together with a nephrotic-range proteinuria.

The biopsy from one of enlarged lymph nodes showed effacement of the architecture with a dark background of cells consisting of numerous small lymphocyte-like cells with scattered larger cells including prolymphocytes and paraimmunoblasts. The predominant cells were slightly larger than normal lymphocytes (Figure 3A) with round nucleolus and clumped chromatin. Only mild nuclear irregularity was noted. The mitotic phase was occasionally observed. Immunohistochemistry showed these cells were positive for CD20, CD79α, CD5 (Figure 3B), and CD23 but negative for CD3, CD45RO, CyclinD1, CD38, and CD138. An important finding was that there were patches of homogeneous hyaline material in the interstitium and vascular walls (Figure 3A), which was verified to be amyloid protein by Congon-red staining (Figure 3C). Immunoassay confirmed that the deposit was positive for kappa but negative for lambda and serum amyloid A protein (Figure 3D-E). The patient was diagnosed as CLL with systemic AL amyloidosis.

Because of unknown reason of worsening of proteinuria and decreasing of the Alb down to 29 g/l after 2 courses of combinative chemotherapy including 2 mg chlorambucil and 30 mg prednisone, a kidney biopsy was performed. The patient's renal tissue submitted for light microscopy consisted of two cores of renal cortex and medulla containing 35 glomeruli. There was no global or segmental sclerosis. All glomeruli showed diffused, eosinophilic and homogeneous material in mesangial area replacing the normal mesangial matrix (Figure 4A). Some extended into the peripheral capillary walls and appeared as large subendothelial deposits or even seemed to be located in the capillary lumen. The deposits were amyloid as shown by strong Congo-red positive staining (Figure 4B) and bright apple green birefringence under polarized light (Figure 4C). The same deposits were found in the interstitium, peritubular space and blood vessel walls. Immunohistochemistry showed that the amyloid was kappa positive but negative for lambda and serum amyloid A protein. Only mild focal tubular atrophy was found. Clusters of lymphocyte-like cells which were CD5 and CD20 positive infiltrated in renal interstitium, occupying less than 30% of the area of the cortical tissue examined (Figure 4D and 4E). The small arteries exhibited mild fibrointimal thickening and the arterioles appeared segmental hyalinosis. Immunofluorescence staining showed faint staining of IgG and IgM along the peripheral capillary in glomeruli while IgA, C3, C1q and fibrinogen were negative. Non-branched fibrils with 10 nm-diameters were detected in mesangium and subendothelial area (Figure 4F) by electronic microscopy. All these histological changes indicated a direct infiltration of the tumor cells in the renal parenchyma together with AL amyloidosis.

Chemotherapy was given by combination of 44 mg fludarabine and 20 mg dexamethasone from July 24, 2008 to September 26, 2008 for 3 courses of treatment. After that, the lymph nodes size decreased and the edema was dramatically ameliorated with decreased serum Cr (200 μmol/L), increased serum albumin (39.96 g/L), declined serum IgM level (2.38 g/L) and slightly reduced 24-hour urinary protein excretion (4.22 g/24 h). However, the patient developed a severe bone marrow depression defined by markedly reduced blood cell count (erythrocytes: 1.66 × 10¹²/L, leukocytes: 0.62 × 10⁹/L, platelet: 21 × 10⁹/L). Then the chemotherapy regimen was adjusted (fludarabine 50 mg, CTX 0.3 g and rituximab 600 mg). After 3 courses of treatment from Nov 27, 2008 to Feb 19, 2009, the patient achieved a satisfactory hematologic response. His serum IgM concentration gradually decreased to the normal level and the monoclonal immunoglobulin was undetectable by serum immunofixation electrophoresis. At the same time, the patient experienced a gradual improvement in clinical status and decrease in the proteinuria and serum creatine. His renal function, urinary protein and serum C3 level were recovered entirely in Sept 2009 (24-hour urinary protein excretion: 139.20 mg/24 h, urine routine test: negative, serum Cr: 121.00 μmol/L, serum C3 level 0.96 g/L).