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*
Department of Pathology, Columbia College of Physicians and Surgeons, New
York, New York
Department of Medicine, Division of Nephrology, Columbia College of
Physicians and Surgeons, New York, New York
Division of Nephrology, Department of Internal Medicine, Morristown
Memorial Hospital/Atlantic Health System, Morristown, New Jersey
Nephrology Division, Baylor University Medical Center, Dallas,
Texas
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Division of Nephrology, Department of Internal Medicine, Hilton Head
Medical Center, Hilton Head Island, South Carolina
¶
Department of Medicine, New York Medical College, New York, New
York
#
Department of Medicine, Division of Nephrology, Medical Center of
Delaware, Newark, Delaware
**
Lehigh Valley Nephrology Associates, Bethlehem, Pennsylvania.
Correspondence to Dr. Vivette D. D'Agati, Department of Pathology, Columbia College of Physicians and Surgeons, 630 W. 168th Street, VC 14-224, New York, NY 10032. Phone: 212-305-7460; Fax: 212-342-5380; E-mail: vddl{at}columbia.edu
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Introduction |
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With the exception of HIV infection, no common epidemiologic features or toxic exposures have been linked to the development of collapsing FSGS. We report the first association of collapsing FSGS with toxicity to a therapeutic agent. The demographic profile of this cohort differs from that for idiopathic collapsing FSGS in that all seven patients were older, Caucasian, and HIV negative and developed collapsing FSGS in the course of active treatment for malignancy. Although the majority of patients had multiple myeloma and received varying types of chemotherapy, with or without radiotherapy, the single unifying factor was prolonged intravenous treatment with high-dose pamidronate (Aredia; Novartis Pharmaceuticals, East Hanover, NJ). Supporting the possibility of dose-related toxicity is the observation that, in most cases, renal disease developed only after doses in excess of the standard recommended dose (90 mg, intravenously [IV], each month) were administered for many months.
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Clinical Histories |
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Patient 2
A 71-yr-old Caucasian woman was diagnosed with multiple myeloma in 1997 and
subsequently was treated with melphalan and prednisone from late 1997 to early
1998. The patient never received a bone marrow transplant or total-body
irradiation, although she received local irradiation to the hip in 1997. The
patient was started on pamidronate at 90 mg IV monthly in September 1998; the
dose was increased to 180 mg monthly in May 1999 and was increased further to
180 mg bimonthly in February 2000. The patient also received thalidomide, at a
mean dose of 600 mg/d, from July 1999 until March 2000. In January 2000, the
patient was started on cyclophosphamide, dexamethasone, etoposide, cisplatin,
and doxorubicin. Serum creatinine increased progressively from 1.2 mg/dl in
February 2000 to 1.5 mg/dl in March, 2.3 mg/dl in April, and 4.2 mg/dl in May.
In May 2000, the patient developed full nephrotic syndrome, with 24-h urinary
protein excretion of 12 g/d, albumin of 2.3 g/dl, cholesterol of 388 mg/dl,
and severe peripheral edema. A renal biopsy was performed in June 2000. After
the biopsy, the patient immediately began renal replacement therapy.
Patient 3
A 50-yr-old Caucasian woman was diagnosed with multiple myeloma in 1996 and
received three cycles of vincristine, doxorubicin, and dexamethasone, followed
by tandem stem cell transplantation. The patient was treated with a short
course of interferon-
in early 1997 but never received total-body
irradiation or thalidomide. In July 1996, she was started on pamidronate at 90
mg IV monthly; this dose was increased to 180 mg IV monthly in January 1998.
In October 1999, the patient had a serum creatinine of 0.5 mg/dl, and
pamidronate therapy was increased to 180 mg IV bimonthly. Subsequently, the
creatinine increased to 2.3 mg/dl in December 1999 and to 2.8 mg/dl in January
2000. At that time, the patient developed full nephrotic syndrome, with 24-h
urinary protein excretion of 5.8 g/d, albumin of 2.8 g/dl, and peripheral
edema. A renal biopsy was performed in January 2000. After 3 mo of follow-up
monitoring, the patient continued to receive pamidronate, had a serum
creatinine of 7.5 mg/dl, and began hemodialysis.
Patient 4
A 53-yr-old Caucasian woman was diagnosed with multiple myeloma and was
given a short course of radiotherapy to treat a plasmacytoma of her seventh
thoracic vertebra in September 1997. She then received vincristine,
doxorubicin, dexamethasone, cyclophosphamide, and melphalan, followed by
tandem autologous stem cell transplants in March 1998 and July 1998. The
patient did not receive total-body irradiation. Pamidronate therapy was
initiated in March 1998, at a dose of 90 mg IV monthly; the dose was increased
to 180 mg monthly in July 1998. In November 1999, the patient developed renal
insufficiency (creatinine, 3.0 mg/dl) and nephrotic syndrome, with 24-h
urinary protein excretion of 14.8 g/d, albumin of 2.5 g/dl, cholesterol of 725
mg/dl, and peripheral edema. The multiple myeloma was believed to be in
clinical remission at that time, and the patient subsequently was maintained
on thalidomide (400 mg/d, started in November 1999) and pamidronate (180 mg
monthly) only. A renal biopsy was performed in April 2000. After the biopsy,
pamidronate therapy was discontinued and the patient was treated with
prednisone. Seven mo later, she had a serum creatinine of 4.3 mg/dl and
remained fully nephrotic.
Patient 5
A 49-yr-old Caucasian woman was diagnosed with infiltrating ductal
carcinoma of the right breast in 1992 and underwent a modified radical
mastectomy and axillary dissection, with no evidence of metastasis. The
patient received three courses of chemotherapy with doxorubicin and
cyclophosphamide, ending in February 1993. She was free of disease until May
1997, when she was diagnosed with infiltrating ductal carcinoma of the left
breast. Despite the discovery of multiple bone metastases, the patient elected
to undergo a modified radical left mastectomy. In June 1997, she had a serum
creatinine of 0.6 mg/dl and was started on pamidronate (90 mg IV monthly). In
December 1997, she underwent bilateral oophorectomy for estrogen depletion,
followed by sequential hormonal therapies, including tamoxifen, fulvestrant,
and anastrazole. In October 1998, the pamidronate dose was increased to 180 mg
IV monthly. In January 1999, Herceptin (Genentech, South San Francisco, CA)
therapy at 110 mg IV every week was initiated. In June 1999, dura-based brain
metastases necessitated gamma knife surgery and whole-brain irradiation. In
May 2000, the patient developed nephrotic syndrome and renal insufficiency,
with 24-h urinary protein excretion of 15 g/d, albumin of 1.9 g/dl, severe
peripheral edema, and serum creatinine of 4.8 mg/dl. A renal biopsy was
performed in May 2000. Subsequently, the pamidronate therapy was discontinued
and the patient was treated with prednisone. Five mo later, she remained fully
nephrotic, with a serum creatinine of 4.2 mg/dl.
Patient 6
A 76-yr-old Caucasian woman was diagnosed with multiple myeloma in 1982.
She was treated with melphalan, prednisone, and vincristine from 1982 to 1983
and with melphalan and prednisone from 1987 to 1988 and again from 1992 to
1993. The patient also received local irradiation to her thoracic and lumbar
spine in 1983 and to her left hip in 1989. She never received a bone marrow
transplant, total-body irradiation, or thalidomide therapy. In June 1998, the
patient had a serum creatinine of 1.2 mg/dl and was started on pamidronate at
90 mg IV monthly. Her creatinine subsequently increased to 1.5 mg/dl in
December 1998, to 2.4 mg/dl in June 1999, and to 5.0 mg/dl in September 1999.
In September 1999, the patient became fully nephrotic, with 24-h urinary
protein excretion of 8 g/d, albumin of 3.6 g/dl, cholesterol of 334 mg/dl, and
peripheral edema. A renal biopsy was performed in September 1999. Despite
discontinuation of pamidronate therapy and treatment with steroids, 1 mo later
the patient had a creatinine of 8 mg/dl and began hemodialysis.
Patient 7
A 77-yr-old Caucasian man was diagnosed with multiple myeloma in 1995,
after back pain and discovery of lytic lesions in the T5 vertebra and left
rib. He was treated with localized irradiation and one course of chemotherapy
with prednisone and cyclophosphamide. The patient never received a bone marrow
transplant or total-body irradiation. In July 1996, the patient was started on
pamidronate at 60 mg IV monthly. He had a baseline serum creatinine of 1.2
mg/dl in July 1996 and again in January 2000. In July 2000, the patient
developed renal insufficiency and full nephrotic syndrome, with a serum
creatinine of 1.6 mg/dl, 24-h urinary protein excretion of 5.4 g/d, serum
albumin of 3.5 g/dl, and peripheral edema. A renal biopsy was performed in
August 2000. After the biopsy, pamidronate therapy was discontinued. After 3
mo of follow-up monitoring, the patient remained nephrotic, with a creatinine
of 1.4 mg/dl.
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Materials and Methods |
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, 
, fibrinogen, and albumin (Dako Corp.,
Carpinteria, CA). In six of the seven cases, glomerular tissue was available
for ultrastructural evaluation. Paraffin-embedded tissue was available for immunohistochemical analysis for the five biopsies processed at Columbia Presbyterian Medical Center. For synaptopodin staining, sections were heated in a microwave oven and then overlaid sequentially with 10% normal horse serum (Vector Laboratories, Burlingame, CA), synaptopodin-specific antibody (1:1; Maine Biotechnology, Portland, ME), and biotinylated horse anti-mouse antibody (1:100; Vector Laboratories), followed by avidin-biotin complex (Vector Laboratories) and diaminobenzidine, as described previously (9). Staining for Ki-67 (1:400; Immunotech, France) was performed with a Dako autostainer, using the Dako Envision Plus detection system (Carpinteria, CA), horseradish peroxidase, and diaminobenzidine substrate.
Patients' charts were reviewed for age, gender, race, type of malignancy,
detailed history of oncologic treatments, and parameters of renal function.
Nephrotic syndrome was defined by the presence of proteinuria of >3.5 g/d,
hypoalbuminemia (
3.5 g/dl), and peripheral edema. In each case, an attempt
was made to document and correlate the time course of the development of renal
insufficiency and nephrotic syndrome with different forms of oncologic
treatment.
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Results |
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All seven patients were treated with pamidronate for 15 to 48 mo before renal biopsy. Although all began therapy at or below the recommended dose of 90 mg IV monthly (10,11) (for a mean 16.9 mo), the dose subsequently was increased for five of the seven patients, to 180 mg monthly in two patients and to 360 mg monthly in three patients. In these five patients, the elevated dose was administered for a mean of 14.8 mo before renal biopsy. One patient received the standard dose of 90 mg IV monthly for 15 mo, whereas another received 60 mg IV monthly for 48 mo. No patient had a serum creatinine of >1.2 mg/dl before the initiation of pamidronate therapy, and all developed renal insufficiency and nephrotic syndrome while they were maintained on continuous, monthly, IV pamidronate therapy. Of note, the pamidronate dosage was not altered during the progression of renal insufficiency.
At the time of renal biopsy, all patients had evidence of renal insufficiency and full nephrotic syndrome (Table 1). The mean serum creatinine was 3.6 mg/dl (range, 1.6 to 5.0 mg/dl), and the mean 24-h urinary protein excretion was 12.4 g/d (range, 5.4 to 26 g/d). All patients were hypoalbuminemic, and all had peripheral edema.
After renal biopsy, one patient (patient 2) immediately began dialysis and three additional patients (patients 1, 3, and 6) required dialysis within 1 to 3 mo. Of note, two of the three patients who experienced disease progression continued to receive pamidronate; one patient also was treated with a course of prednisone. In contrast, pamidronate therapy was discontinued in the remaining three patients (patients 4, 5, and 7), of whom two had decreases in serum creatinine over the course of 3 to 7 mo and none required renal replacement therapy.
The renal biopsy findings in patients with pamidronate-associated collapsing FSGS are highlighted in Table 2. All seven biopsies displayed lesions of collapsing FSGS characterized by implosive retraction of the glomerular basement membranes and hyperplasia of the overlying podocytes, some of which contained intracytoplasmic protein resorption droplets (Figure 1, A and B). Diffuse podocyte swelling was frequently noted in glomeruli without FSGS lesions. The mean number of glomeruli sampled was 17.1 (range, 4 to 35), and the mean number of glomeruli with FSGS lesions was 3.4 (range, 2 to 5). All biopsies displayed diffuse severe tubular degenerative changes, including luminal ectasia, epithelial simplification, loss of the brush border, nuclear pleomorphism with prominent nucleoli, cytoplasmic vacuolization, and focal apoptosis (Figure 1C). The degree of tubular atrophy and interstitial fibrosis ranged from mild to severe, with focal tubular microcyst formation.
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In electron microscopic studies, the podocytes displayed diffuse loss of their highly differentiated cytoarchitecture, including the disappearance of primary processes and extensive foot process effacement over a mean of 84% (range, 60 to 100%) of the glomerular capillary surface area (Figure 1D). Many podocytes had increased organellar content, including numerous small mitochondria. The proximal tubular epithelium also displayed extensive degenerative changes, including epithelial simplification, loss of the apical brush border, and dilation of the endoplasmic reticulum (Figure 1E). A rare endothelial tubuloreticular inclusion was identified in only one of six cases.
Immunofluorescence studies revealed segmental tuft staining for C3 and IgM in two biopsies (patients 4 and 7). The absence of deposits was confirmed at the ultrastructural level in all six biopsies studied by electron microscopy. In all seven biopsies, there was no evidence of amyloidosis, myeloma cast nephropathy, light chain deposition disease, or other forms of myeloma-associated nephropathy. No biopsy revealed evidence of radiotherapy- or chemotherapy-associated thrombotic microangiopathy or urate nephropathy (tumor lysis syndrome).
Immunohistochemical staining for Ki-67, a proliferation marker, was positive in many tubular epithelial cells (up to 11/tubule) in all cases and in scattered visceral epithelial cells (up to 4/glomerulus) in three of the four cases studies (Figure 2, A and B). In comparison, staining in control kidneys was absent in glomeruli and focally positive in rare (<0.1%) tubular epithelial cells. High-intensity expression of synaptopodin, a podocyte-specific, actin-associated, cytoskeletal protein, was identified in a podocyte distribution in normal control samples (Figure 2C). Synaptopodin expression was reduced in the four study cases, with the most extensive loss of expression in glomeruli with collapsing FSGS lesions (Figure 2D).
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The efficacy of pamidronate in patients with osteolytic metastases has been established. In a large, placebo-controlled study of 392 patients with stage III multiple myeloma, nine monthly cycles of 90 mg IV of pamidronate were shown to reduce skeletal complications and bone pain and to improve quality of life (10). When the study was extended to 21 monthly cycles of therapy, similar results were obtained (13). Of note, four of the 198 patients who received pamidronate were removed from the trial because of worsening renal insufficiency, although data on renal histologic evaluation were not provided (13). Similarly, a large, placebo-controlled study was performed on 382 women with stage IV breast cancer and osteolytic metastases (11). The study population received up to 24 cycles of 90 mg of pamidronate, administered IV, every 3 to 4 wk and experienced a significant decrease in skeletal complications. In that study, a single patient discontinued pamidronate treatment because of renal failure, which was believed to be "possibly related to the study drug" (11).
After reaching the systemic circulation, bisphosphonates either bind to bone or are excreted unchanged via the kidneys. Animal models have shown that the clearance of bisphosphonates can exceed the GFR, suggesting active tubular secretion. This observation provides the basis for slow intravenous infusion of pamidronate over several hours, in an attempt to prevent toxic concentrations from being reached at the level of the proximal tubule (14). Despite slow infusion, human studies demonstrated a 1 to 8% incidence of elevation in serum creatinine after administration of bisphosphonates (15). Those studies also suggested that the newer, more potent bisphosphonates are effective at lower doses, therby producing less renal toxicity (i.e., 2% for pamidronate) (15).
Multiple lines of evidence point to pamidronate as the etiologic agent producing collapsing FSGS in our cohort of patients. First is the previously established, albeit infrequent, renal toxicity associated with this agent (11,13,15). The recommended dose of pamidronate in humans is 0.4 to 1.5 mg/kg, based in part on rat studies that showed no nephrotoxicity at comparable levels of up to 1.5 mg/kg (16). However, dose-dependent nephrotoxicity was observed in rats given higher doses (5.0 to 50.0 mg/kg) (16). Although a short-term study on 12 patients treated with pamidronate at 90 mg IV weekly for 4 consecutive weeks revealed no evidence of nephrotoxicity (17), no studies have addressed the potential nephrotoxicity of long-term use at higher-than-standard doses. As inferred from data in rats, pamidronate dosing schedules that are 2 to 4 times greater than recommended are likely to increase the risk of renal toxicity. The renal biopsy findings of sparse interstitial inflammatory infiltrates, without inflammation within tubules ("tubulitis") or eosinophils, and the lack of demonstrable antibodies in immunofluorescence analyses suggest that pamidronate acts as an epithelial toxin that targets both the podocyte and the tubular epithelium, rather than via an immunologic or allergic mechanism.
The clinical profiles of our patients also provide strong evidence of
high-dose pamidronate being the etiologic agent in collapsing FSGS. The
occurrence of the distinctive pattern of collapsing FSGS in a cohort of
predominantly older and exclusively Caucasian individuals, all with a history
of malignancy, is striking and is in sharp contrast to the predominantly
young, African-American population among whom idiopathic collapsing FSGS
typically is observed. No patient had evidence of multiple myeloma-associated
nephropathy (e.g., amyloidosis, light chain deposition disease),
radiotherapy- or chemotherapy-associated thrombotic microangiopathy, or urate
nephropathy (tumor lysis syndrome). Although patients were exposed to a
variety of potent nephrotoxins, including total-body irradiation and
cisplatin, the only potential nephrotoxin common to all patients was
pamidronate. Furthermore, the typical patterns of nephrotoxicity observed with
these other agents are thrombotic microangiopathy (total-body irradiation) and
acute tubular injury without glomerular pathologic features (cisplatin). The
only chemotherapeutic agent that has been implicated in FSGS is
interferon-, which was administered to only one of the seven patients
and which has not been associated with the collapsing form of FSGS
(18).
Temporally, the development of proteinuria and renal insufficiency closely paralleled the administration of pamidronate in escalating doses that exceeded the recommended levels. All seven patients had normal renal function before the start of pamidronate therapy. Renal insufficiency and nephrotic syndrome did not develop until the dosage was increased to 180 mg/mo in patients 4 and 5 and to 360 mg/mo in patients 1, 2, and 3. Two patients (patients 6 and 7) never received pamidronate at greater than the recommended dose of 90 mg/mo. Furthermore, two of the three patients in whom pamidronate was discontinued after biopsy had decreases in serum creatinine at 3 and 5 mo; all three patients have not yet required dialysis.
The concept of a drug-induced form of FSGS is not unique; in animal models, FSGS can be induced by treatment with doxorubicin (19,20) or puromycin aminonucleoside (21). In rats, a single intravenous dose of puromycin aminonucleoside produces a glomerulopathy that initially resembles minimalchange disease but evolves into FSGS with time (21). In contrast, a single injection of doxorubicin can produce an animal model of FSGS (20), although this effect is more consistently observed after two successive doxorubicin administrations (20).
In humans, drug-induced nephrotic syndrome related to minimal-change
disease or FSGS is uncommon but has been reported with interferon-,
nonsteroidal anti-inflammatory drugs, and lithium. In none of those cases have
collapsing FSGS lesions been observed
(18,22).
Within the spectrum of FSGS, collapsing FSGS represents the most severe
morphologic expression. Evidence from both HIV-associated and idiopathic forms
indicates a direct podocyte injury, whereby podocytes enter the cell cycle and
lose their differentiated phenotype, with reduced expression of maturity
markers such as Wilm's tumor protein WT-1, common acute lymphoblastic leukemia
antigen, podocalyxin, and synaptopodin
(9). The same findings of
increased podocytic proliferation index and reduced expression of synaptopodin
observed in our patients with collapsing FSGS after high-dose pamidronate
therapy suggest a direct podocyte effect. Although tubular toxicity was
proposed previously for high-dose pamidronate, tubular injury alone is
insufficient to account for the collapsing FSGS and nephrotic syndrome. The
severe tubular and glomerular alterations observed after high-dose pamidronate
therapy suggest combined tubular epithelial and podocyte toxicity. Similar
broad renal epithelial toxicity has been observed in HIV-associated
nephropathy, in both human and transgenic models
(23,24).
The potential mechanism of renal epithelial toxicity may involve cellular
effects similar to those documented in osteoclasts. A major action of
bisphosphonates is to mimic the calcium-chelating property of inorganic
pyrophosphate, an endogenous regulator of bone mineralization, thereby
inhibiting bone dissolution via binding to Ca2+ in hydroxyapatite
of the bone matrix (25).
However, in addition to these physicochemical properties, bisphosphonates are
internalized by osteoclasts and exert a number of cellular effects. The
nitrogen-containing bisphosphonates, such as pamidronate, can inhibit the
intracellular mevalonate pathway required for the posttranslational lipid
modification (i.e., prenylation) of small GTPases
(26). By anchoring the GTPases
in cell membranes, lipid prenyl groups ensure the correct subcellular
compartmentalization and functioning of GTPases in a variety of cellular
processes, including integrin signaling, endosomal trafficking, membrane
ruffling, and apoptosis
(25,27,28,29,30).
Through incorporation into ATP analogues, bisphosphonates also can impair cell
energetics via inhibition of ATP-dependent metabolic pathways
(31). At nontoxic doses,
bisphosphonates have been shown to disrupt the osteoclast cytoskeleton by
inhibiting the assembly of actin rings, leading to loss of the osteoclast
ruffled border (32). The
unique cytoarchitecture of osteoclasts and podocytes (both of which have a
highly differentiated cytoskeleton with specialized processes and motility),
coupled with the high drug levels attained in bone and kidney, may explain the
cell-specific toxicities observed. Finally, via their homology to certain
T-cell ligands, bisphosphonates have been reported to stimulate 
T cells, leading to increased production of interferon- and other
cytokines (33). A potential
mechanism of podocyte injury by T-cell-derived lymphokines or
"permeability factors" has been proposed for idiopathic FSGS
(34,35).
Pamidronate is a widely used and important therapeutic agent in the treatment of hypercalcemia of malignancy and osteolytic metastases. Large-scale, long-term studies are necessary to establish the safety of this agent when it is used at doses that exceed the recommended levels, especially in patients with renal insufficiency. Because of the possible direct podocyte toxicity of this drug, periodic evaluations for proteinuria, in addition to measurements of renal function, may provide a useful means to monitor patients at risk for developing pamidronate nephrotoxicity.
High-dose pamidronate administration seems to be the first drug-related
cause of collapsing FSGS, and pamidronate joins interferon- and lithium
as potential inducers of FSGS. In patients with multiple myeloma, renal
biopsies often are performed to assess the pathogenesis of proteinuria and/or
renal insufficiency. Although chemotherapeutic agents may be associated with
acute tubular injury or thrombotic microangiopathy, they do not produce
nephrotic syndrome. In contrast, the presence of full nephrotic syndrome in
this clinical setting usually heralds the development of amyloidosis or light
chain deposition disease. The causes of nephrotic syndrome in this patient
population now may be expanded to include collapsing FSGS after treatment with
high-dose pamidronate.
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Acknowledgments |
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T cells by aminobisphosphonates and induction of anti-plasma
cell activity in multiple myeloma. Blood96
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J.-J. Body, T. Pfister, and F. Bauss Preclinical Perspectives on Bisphosphonate Renal Safety Oncologist, October 1, 2005; 10(suppl_1): 3 - 7. [Abstract] [Full Text] [PDF]
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J. Balla The Issue of Renal Safety of Zoledronic Acid from a Nephrologist's Point of View Oncologist, May 1, 2005; 10(5): 306 - 308. [Full Text] [PDF]
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 K. D. Miller, L. I. Chap, F. A. Holmes, M. A. Cobleigh, P. K. Marcom, L. Fehrenbacher, M. Dickler, B. A. Overmoyer, J. D. Reimann, A. P. Sing, et al. Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer J. Clin. Oncol., February 1, 2005; 23(4): 792 - 799. [Abstract] [Full Text] [PDF]
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B. D. Humphreys, R. J. Soiffer, and C. C. Magee Renal Failure Associated with Cancer and Its Treatment: An Update J. Am. Soc. Nephrol., January 1, 2005; 16(1): 151 - 161. [Full Text] [PDF]
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S. Lee, D. Glicklich, and M. Coco Pamidronate used to attenuate post-renal transplant bone loss is not associated with renal dysfunction Nephrol. Dial. Transplant., November 1, 2004; 19(11): 2870 - 2873. [Abstract] [Full Text] [PDF]
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