Focal segmental glomerulosclerosis (FSGS) is a histological. Reversibility of pamidronate-associated glomerulosclerosis

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1 Reversibility of pamidronate-associated glomerulosclerosis Meera Shreedhara, MD, Andrew Z. Fenves, MD, Diana Benavides, MD, and Marvin J. Stone, MD, MACP Bisphosphonates such as pamidronate are widely used in the treatment of patients with lytic bony lesions secondary to breast cancer or multiple myeloma, yet they have been associated with deterioration of renal function and histopathological changes in the kidney. There have been recent reports associating the use of pamidronate with the development of the collapsing variant of focal segmental glomerulosclerosis (CFSGS), a rapidly progressive variant of focal segmental glomerulosclerosis that leads to end-stage renal disease. We describe five patients who developed worsening renal function, proteinuria, and nephrotic syndrome while taking pamidronate; three of them had biopsy-proven CFSGS. Pamidronate was discontinued, and a longitudinal follow-up was performed for 10 to 23 months. One patient was able to discontinue hemodialysis, and all patients experienced improvement in renal function and a decrease in proteinuria. In some patients who develop pamidronate-associated CFSGS, renal damage appears to be reversible if the syndrome is recognized early and pamidronate is stopped. Focal segmental glomerulosclerosis (FSGS) is a histological pattern seen in many glomerular diseases. The incidence of FSGS has increased in the last 2 decades, particularly in African American patients, and hence there has been more interest in the pathogenesis and classification of this entity. Some investigators have focused on secondary causes and histologic variants of FSGS, as well as the differences in approach to treatment and differences in clinical outcome (1 3). D Agati and colleagues described five morphologic variants of FSGS, as observed with light microscopy. These include classic FSGS (not otherwise specified) and the perihilar, cellular, tip, and collapsing variants (4 7). Collapsing focal segmental glomerulosclerosis (CFSGS) is a distinct clinicopathological entity separate from FSGS. It was first reported in young African American men with HIV infection (6). The most common presentation of CSFGS is nephrotic syndrome, renal insufficiency, and hypertension. Clinically, the collapsing variant of FSGS is distinguished from other variants of FSGS by the presence of more severe nephrotic syndrome, a more accelerated course to renal failure, and a greater resistance to immunosuppressive therapy (5, 7). Recently, there have been reports of CFSGS occurring in association with the use of pamidronate (8 10). It is thought Proc (Bayl Univ Med Cent) 2007;20(3): that discontinuation of pamidronate might improve the renal prognosis in these patients. However, to date there have not been any reports on the follow-up of these patients to support this view. We report on five patients with CFSGS believed to be secondary to pamidronate whose renal function improved once pamidronate was discontinued. Methods We identified three patients who developed biopsy-proven CFSGS associated with the long-term use of pamidronate. Two other patients developed azotemia and new-onset nephrotic syndrome while taking monthly pamidronate and were presumed to have CFSGS on clinical grounds. Pamidronate was discontinued in all patients at the time of diagnosis. All five patients had cancer and were diagnosed and treated for their malignancies at our institution. Two renal biopsies were performed and processed at our institution; the third biopsy was performed at an outside facility and reviewed in consultation with our pathologists. Patients charts were reviewed for age, gender, race, type of malignancy, prior therapies, and parameters for renal function. The review was approved by the institutional review board. Each patient s cumulative pamidronate dose was estimated, and the patients were followed longitudinally for 10 to 23 months after pamidronate was discontinued. The parameters of nephrotic syndrome that were considered were proteinuria, hypoalbuminemia, and peripheral edema. Results Table 1 summarizes the clinical features of the five patients, all women, who ranged in age from 50 to 80 years. Four had breast cancer, and one had multiple myeloma; none were HIV positive. Four patients had received prior treatment with chemotherapeutic agents. The patients took pamidronate for 9 months From the Division of Hematology/Oncology (Shreedhara, Stone) and the Division of Nephrology (Fenves), Department of Internal Medicine, and the Department of Pathology (Benavides), Baylor University Medical Center and Baylor Charles A. Sammons Cancer Center, Dallas, Texas. Corresponding author: Andrew Z. Fenves, MD, Dallas Nephrology Associates, 3601 Swiss Avenue, Dallas, TX ( fenvesa@dneph.com). 249

2 Table 1. Clinical characteristics of patients with pamidronate-induced focal segmental glomerulosclerosis Variable Patient 1 Patient 2 Patient 3 Patient 4* Patient 5* Age (years) at initial presentation Sex F F F F F Race Caucasian Caucasian Caucasian Caucasian Caucasian Primary tumor Breast cancer Multiple myeloma Breast cancer Breast cancer Breast cancer Chemotherapy Etoposide, Doxorubicin, paclitaxel, Doxorubicin, Doxorubicin, cyclophosphamide melphalan capecitabine Hormonal therapy Tamoxifen, fulvestrant, Tamoxifen, anastrozole, Anastrozole, fulvestrant Tamoxifen anastrozole exemestane, fulvestrant Metastases to bone Yes No Yes Yes Yes Monthly intravenous pamidronate dose (mg) Length of pamidronate use Estimated cumulative dose (mg) 90 for 1 year; 180 for 2 years for 3 years; 60 for 5 years 3 years 9 months 10 months 5 years 8 years a b a b c d Figure 2. Biopsy results for patient 2. (a) Focal segmental glomerulosclerosis with changes suggestive of collapsing glomerulopathy. Hematoxylin-eosin stain, 100. (b) Collapsing glomerulopathy is shown through segmental collapse of capillary loops and mild visceral epithelial hypertrophy. Hematoxylin-eosin stain, 400. Figure 1. Biopsy results for patient 1 showing collapsing glomerulopathy. (a, b) The glomerulus has extensive global collapse of capillaries, with hypertrophy of overlying epithelial cells. There is less expansion of the mesangial matrix and adhesion formation than would be found in typical focal segmental glomerulosclerosis. Periodic acid Schiff stain, 400. (c, d) Global collapse of the glomerular tuft, mesangial hypercellularity, and hypertrophy of the visceral epithelium are present. Periodic acid Schiff stain, 100. to 8 years, starting with the standard dose of 90 mg intravenously. Patient 1 switched to a 180-mg dose after 1 year. After taking pamidronate, the patients presented with nephrotic-range proteinuria, peripheral edema, hypoalbuminemia, and worsening renal function. Three patients had renal biopsy findings consistent with CFSGS (Figures 1 and 2). A biopsy was not done in two other patients because of comorbid medical conditions. Pamidronate was discontinued at the time of diagnosis of CFSGS. After pamidronate was discontinued, all five patients had a complete or partial resolution of proteinuria and improved renal function (Table 2). Serum creatinine levels markedly improved in each patient as well. Patient 3 was started on dialysis and was able to discontinue it after a month; she was also able to taper off prednisone. Dialysis was considered in patient 2, but her proteinuria, serum albumin level, and serum creatinine level quickly improved. Patient 3 did not have a complete resolution, but by the time of biopsy her serum creatinine and albumin levels were already improving. In patient 5, renal function was substantially improved after pamidronate was discontinued, but it did not go back to baseline. All patients were receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Clinical Histories Patient 1 A Caucasian woman was diagnosed with infiltrative ductal carcinoma of the right breast at the age of 50 in She was treated with a modified radical mastectomy with axillary dissection followed by three courses of doxorubicin and cyclophosphamide in In May 1997 she was diagnosed with infiltrating ductal carcinoma of the left breast with multiple bone metastases. She underwent a modified left mastectomy. At this time her serum creatinine level was 1.6 mg/dl. She was 250 Baylor University Medical Center Proceedings Volume 20, Number 3

3 Table 2. Renal follow-up of patients after discontinuation of pamidronate Variable Patient 1 Patient 2 Patient 3 Patient 4* Patient 5* Baseline serum creatinine (mg/dl) Renal status at diagnosis Serum creatinine (mg/dl) Serum albumin (mg/dl) Proteinuria (g/24 h) (est.) 8.7 Renal status at peak of disease Serum creatinine (mg/dl) Serum albumin (mg/dl) Proteinuria (g/24 h) Length of follow-up (months) Renal status at end of follow-up Serum creatinine (mg/dl) Serum albumin (mg/dl) Proteinuria (g/24 h) NM Dialysis No No Yes No No Nephrotic syndrome after follow-up Improved Improved Improved Improved Improved *Patients 4 and 5 did not have a renal biopsy. NM indicates not measured; est., estimated. started on intravenous pamidronate 90 mg monthly. Subsequently she underwent bilateral oophorectomy and hormonal therapy including tamoxifen, fulvestrant, and anastrozole. Because of worsening bone pain, her pamidronate was increased to 180 mg monthly. In June 1999, she developed brain metastases that required Gamma Knife surgery and radiation. In May 2000, the patient developed nephrotic syndrome with renal insufficiency. She had proteinuria of 15 g/24 h, a serum albumin level of 1.9 mg/dl, a serum creatinine level of 4.8 mg/dl, and peripheral edema. Renal biopsy revealed CFSGS (Figure 1). Pamidronate was discontinued, and she was treated with prednisone. In November 2000 she remained nephrotic, with a serum creatinine level of 4.2 mg/dl. Initiation of dialysis was considered. Her serum creatinine level then decreased to 3.4 mg/dl in February 2001, to 2.5 mg/dl in March 2001, and to 1.8 mg/dl in April In May 2001, almost a year after pamidronate was stopped, her serum creatinine level was back to her baseline at 1.6 mg/dl. The patient s serum albumin level in April 2001 was 3.6 mg/dl, and her peripheral edema had completely resolved. Subsequently she developed progressive brain metastases for which she received paclitaxel and intravenous dexamethasone for a month for palliation. In April 2002 she was found to have new brain metastases. Her serum creatinine level was 2.2 mg/dl at that time. She was placed on hospice care and died in June An autopsy was not performed. Patient 2 A Caucasian woman with a long history of rheumatoid arthritis and Sjögren syndrome was hospitalized in March 2003, at the age of 62, for hypercalcemia and acute renal failure. Her serum creatinine level peaked at 3.0 mg/dl. She was diagnosed with IgA multiple myeloma with no evidence of Bence Jones proteinuria. At the time of discharge, her serum creatinine level was 1.6 mg/dl. She was treated with etoposide and cyclophosphamide. In September 2003 she received high-dose melphalan and then underwent an autologous stem cell transplant. She attained complete remission. In March 2004, the patient was prescribed pamidronate for bone pain. By December 2004 her serum creatinine level had risen to 2.3 mg/dl, and her albumin level had begun to fall. The pamidronate was stopped. In the subsequent months, her serum creatinine level increased to 3.4 mg/dl, and her albumin level decreased to 2.0 mg/dl. A workup for nephrotic syndrome was conducted; the antinuclear antibody test result was negative, with no M spike and normal C3 and C4 levels. She had proteinuria of 5 g/24 h. Due to persistent nephrotic syndrome, the patient underwent a renal biopsy in May 2005 (Figure 2). The biopsy showed advanced global sclerosis of many glomeruli. However, a few surviving glomeruli showed features of collapse and wrinkling, consistent with the diagnosis of FSGS. There was no evidence of cast nephropathy in the kidney. By this time her serum creatinine level had already decreased to 2.9 mg/dl, and her albumin level was up to 3.1 mg/dl. In January 2006 her proteinuria was 2.3 g/24 h. Patient 3 A 60-year-old Caucasian woman with a 6-year history of well-controlled hypertension and diabetes mellitus was diagnosed with right-sided breast cancer with bone metastases in June She was initially treated with anastrozole and then switched to fulvestrant in March She was started on pamidronate at the time of diagnosis. She presented in August 2004 with nephrotic syndrome. Her serum creatinine level was 1.9 mg/dl, an increase from her baseline of 1.4 mg/dl. Her 24-hour urine specimen contained 26 g of protein. Her creatinine clearance was 47 ml/min. Pamidronate was stopped, and she was started on furosemide and prednisone 60 mg every other day. Renal biopsy showed CFSGS. Her proteinuria decreased to 20 g/24 h in September 2004, but her edema worsened and her creatinine clearance was down to 40 ml/min. The furosemide dosage was increased, and she was started on losartan. Later that month she was hospitalized for worsening edema and symptoms of uremia; her creatinine clearance at that point was 14 ml/min. Hemodialysis was initiated and was continued for a month. July 2007 Reversibility of pamidronate-associated glomerulosclerosis 251

4 Subsequently she was also tapered off prednisone. In December 2004, her serum creatinine level was down to 1.5 mg/dl. By October 2005, her albumin level was 3.5 mg/dl, and proteinuria was 5.4 g/24 h. Patient 4 A Caucasian woman was diagnosed with left breast cancer in 1987, at the age of 80 years. She underwent a radical mastectomy and was treated with chemotherapy and then tamoxifen for 7 years. In 1995 she was found to have bone metastases. In 1996 she was started on intravenous pamidronate 90 mg monthly. She also developed a pulmonary embolus and was placed on anticoagulation therapy with warfarin. In April 2004, her serum creatinine level was 0.9 mg/dl. By June 2004, it had risen to 1.1 mg/dl and by August 2004, to 1.4 mg/dl. Around this time the patient was noted to have 3+ proteinuria. Using a spot urine protein to creatinine ratio, her proteinuria was 1.2 g/24 h. Based on the patient s clinical picture, it was presumed that she had pamidronate-associated FSGS, and pamidronate was stopped. Because of her age and comorbidities, a renal biopsy was not performed. With no other intervention, by May 2005, her serum creatinine level decreased to 0.8 mg/dl and her proteinuria decreased to 0.5 g/24 h. Patient 5 A Caucasian woman with a long-standing history of hypertension was diagnosed with bilateral breast cancer with lymph node involvement in 1992, at the age of 57. She underwent bilateral mastectomy and then received six cycles of chemotherapy with doxorubicin and paclitaxel. She was then started on tamoxifen. In 1994 she was found to have bone metastases and was prescribed additional agents, including anastrozole, exemestane, fulvestrant, and capecitabine. In 1997 she was started on intravenous pamidronate 90 mg monthly, which after 3 years was reduced to 60 mg monthly. Her baseline serum creatinine level was 0.9 mg/dl. In July 2004, she was found to have a serum creatinine level of 2.3 mg/ dl, a serum albumin level of 3.2 mg/dl, creatinine clearance of 26 ml/min, and proteinuria of 8.7 g/24 h. Based on clinical grounds, pamidronate-induced CFSGS was diagnosed. Pamidronate was discontinued, but a renal biopsy was not performed. Her serum creatinine level peaked at 3.5 mg/dl, and her albumin level went down to 2.8 mg/dl. Twelve months after pamidronate was stopped, her serum creatinine level was 2.3 mg/dl, her albumin level was 3.9 mg/dl, and her estimated proteinuria was 2.4 g/24 h. Discussion CFSGS is characterized by marked wrinkling and collapse of glomerular basement membranes and hypertrophy and hyperplasia of overlying podocytes. This disease was first described by Weiss et al in 1986 (11). Compared with other types of FSGS, CSFGS leads to higher mean serum creatinine levels and 24-hour protein excretion, with a markedly worse renal survival (5, 7). Recently, Markowitz et al documented the development of CFSGS after 15 to 48 months of treatment with highdose pamidronate (8, 9). Based on their activity in inhibiting bone resorption by direct and indirect actions on osteoclasts, inhibiting the production of cytokines such as interleukin-6 by bone marrow stromal cells, and possibly altering tumor cell adhesion to the stroma (10), bisphosphonates such as pamidronate have been used in the treatment of multiple myeloma, tumor-associated osteolysis, hypercalcemia, Paget s disease, and osteoporosis (12, 13). These drugs are excreted unchanged via the kidneys, and the high drug levels attained in the kidneys may cause renal toxicity through a mechanism similar to that described in osteoclasts (10). The suggested pathogenesis for the pamidronate-associated CFSGS was a primary injury to the podocytes leading to altered cell cycle regulation and reversion to an immature cellular phenotype (8). An increasing number of observations implicates mitochondrial pathological processes in podocyte damage (14, 15). Amino-containing bisphosphonates like pamidronate are not metabolized to cytotoxic compounds but inhibit enzymes of the mevalonate pathway, which results in the activation of mitochondrial capase-3-like enzymes. The latter is considered to lead to apoptotic cell death (14, 15). For idiopathic CFSGS, response to treatment with corticosteroids and immunosuppressive therapy has been poor (7). There have been no other reports on the follow-up of patients with pamidronate-associated FSGS following the discontinuation of the bisphosphonate. Among our five patients four with breast cancer and one with multiple myeloma four showed significant improvement in proteinuria after the pamidronate was discontinued. Serum creatinine levels markedly improved in each patient as well. Patient 3 was able to discontinue dialysis after a month once the drug was stopped. She was also able to taper off her prednisone. Dialysis was also considered in patient 2, but the improvements in her proteinuria, serum albumin level, and serum creatinine level made that step unnecessary. Patient 3 did not have a complete resolution, but by the time of biopsy her serum creatinine and albumin levels were already improving. Patient 5 had a significant improvement in renal function after pamidronate was discontinued but did not return to baseline levels. All the patients were on an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The most definitive diagnosis of CFSGS in this setting is obtained by a renal biopsy. When patients with breast cancer present with worsening renal function, previously the most important concerns were paraneoplastic syndrome and membranous glomerulonephritis. Similarly, in patients with multiple myeloma presenting with declining renal function, Bence Jones proteinuria, light-chain disease, and amyloidosis have been the main concerns. Pamidronate-associated CFSGS is another important complication of therapy in this population and, as this series indicates, may carry a more favorable outcome if recognized early. Important insight into the progression and behavior of this disease can be obtained from the biopsy results for patient 2. It is possible that if pamidronate were stopped earlier in the course 252 Baylor University Medical Center Proceedings Volume 20, Number 3

5 of the disease in patient 2, the progression of sclerosis in the affected glomeruli may have slowed. It is unlikely, however, that glomeruli that are fully sclerosed would recover any function. This probably explains the variable recovery in our patients. Conclusion Pamidronate is increasingly used in patients with multiple myeloma and solid tumors. It is well known that use of this drug causes a collapsing variety of FSGS. Once this condition is recognized and pamidronate is stopped, these patients appear to have a more favorable outcome compared with patients with other forms of CFSGS. Early recognition of this syndrome and prompt discontinuation of pamidronate are critical, as renal impairment appears reversible in some patients. Frequent monitoring of renal function and proteinuria in this subset of patients is warranted. 1. Korbet SM. Treatment of primary focal segmental glomerulosclerosis. Kidney Int 2002;62(6): Korbet SM, Schwartz MM. Primary focal segmental glomerulosclerosis: a treatable lesion with variable outcomes. Nephrology 2001;6(2): Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants. J Am Soc Nephrol 2004;15(8): D Agati V. Pathologic classification of focal segmental glomerulosclerosis. Semin Nephrol 2003;23(2): Detwiler RK, Falk RJ, Hogan SL, Jennette JC. Collapsing glomerulopathy: a clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int 1994;45(5): D Agati V, Suh JI, Carbone L, Cheng JT, Appel G. Pathology of HIVassociated nephropathy: a detailed morphologic and comparative study. Kidney Int 1989;35(6): Valeri A, Barisoni L, Appel GB, Seigle R, D Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study. Kidney Int 1996;50(5): Markowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath S, Kuhn JA, Dratch AD, D Agati VD. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 2001;12(6): Markowitz GS, Fine PL, D Agati VD. Nephrotic syndrome after treatment with pamidronate. Am J Kidney Dis 2002;39(5): Barri YM, Munshi NC, Sukumalchantra S, Abulezz SR, Bonsib SM, Wallach J, Walker PD. Podocyte injury associated glomerulopathies induced by pamidronate. Kidney Int 2004;65(2): Weiss MA, Daquioag E, Margolin EG, Pollak VE. Nephrotic syndrome, progressive irreversible renal failure, and glomerular collapse : a new clinicopathologic entity? Am J Kidney Dis 1986;7(1): Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, Lipton A, Keller A, Ballester O, Kovacs MJ, Blacklock HA, Bell R, Simeone J, Reitsma DJ, Heffernan M, Seaman J, Knight RD. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996;334(8): Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D, Sinoff C, Wheeler H, Simeone JF, Seaman JJ, Knight RD, Heffernan M, Mellars K, Reitsma DJ; Protocol 19 Aredia Breast Cancer Study Group. Longterm prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998;16(6): Sauter M, Julg B, Porubsky S, Cohen C, Fischereder M, Sitter T, Schlondorff D, Grone HJ. Nephrotic-range proteinuria following pamidronate therapy in a patient with metastatic breast cancer: mitochondrial toxicity as a pathogenetic concept? Am J Kidney Dis 2006;47(6): Cheng YY, Huang L, Kumta SM, Lee KM, Lai FM, Tam JS. Cytochemical and ultrastructural changes in the osteoclast-like giant cells of giant cell tumor of bone following bisphosphonate administration. Ultrastruct Pathol 2003;27(6): July 2007 Reversibility of pamidronate-associated glomerulosclerosis 253