RENAL BIOPSY TEACHING CASE
Nephrotic Syndrome After Treatment With Pamidronate
Glen S. Markowitz, MD, Paul L. Fine, MD, and Vivette D. D’Agati, MD
INDEX WORDS: Collapsing focal segmental glomerulosclerosis (FSGS); pamidronate; myeloma; nephrotic syn-
drome.
I N THE SETTING OF multiple myeloma,
major diagnostic considerations in the pa-
tient presenting with nephrotic syndrome include
amyloidosis, monoclonal immunoglobulin depo-
sition disease, and cryoglobulinemic glomerulo-
nephritis.
CASE REPORT
A 68-year-old white woman with no significant past
medical history presented with skeletal pain and anemia in
December 1998. Subsequent evaluation disclosed multiple
compression fractures of the thoracic and lumbar spine and
lytic skull lesions. A bone marrow biopsy revealed 50%
plasmacytosis, diagnostic of multiple myeloma. At that time,
the patient had no significant proteinuria (⬍150 mg/d), and
serum creatinine was 0.9 mg/dL. She immediately began
treatment with pulse dexamethasone administered in 40-mg
doses for 4 consecutive days three times per month for 3
months. At the end of 3 months, repeat bone marrow biopsy
revealed the absence of plasmacytosis. Since that time, the
patient has been treated with pulse dexamethasone for 4
consecutive days once per month, and her myeloma remains
in clinical remission. Her only additional oncologic treat-
ment was thalidomide, administered briefly in July 2001 and
discontinued because of a severe, incapacitating pruritic
rash. The patient has not received a stem cell transplant,
radiation therapy, cisplatin, or melphalan.
The patient’s clinical course has been dominated by
massive and diffuse compression fractures of the thoracic
and lumbar spine. The resultant thoracic deformity has led to
significant restrictive pulmonary disease requiring broncho-
dilator therapy and nocturnal oxygen supplementation. The
mainstay of treatment for the bone disease has been pamidr-
onate (Aredia). In January 1999, the patient began treatment
with pamidronate at a dose of 90 mg intravenously once per
month, which subsequently was increased to 180 mg intrave-
From the Department of Pathology, Columbia College of
Physicians and Surgeons, New York, NY; Division of Nephrol-
ogy, Department of Internal Medicine, Morristown Memo-
rial Hospital–Atlantic Health System, Morristown, NJ.
Received and accepted as submitted December 18, 2001.
Address reprint requests to Glen S. Markowitz, MD,
Department of Pathology, Columbia College of Physicians
and Surgeons, 630 West 168th Street, VC 14-224, New York,
NY 10032. E-mail: vdd1@columbia.edu
© 2002 by the National Kidney Foundation, Inc.
0272-6386/02/3905-0025$35.00/0
doi:10.1053/ajkd.2002.32797
1118 American Journal of Kidney Diseases, Vol 39, No 5 (May), 2002: pp 1118-1122
nously once per month in May 1999, then to 180 mg
intravenously twice per month in March 2000. At that time,
she had a creatinine of 0.9 mg/dL and a 24-hour urine
protein of 105 mg/d. In June 2000, her 24-hour urine protein
increased to 2.1 g/d. In August, the patient had a 24-hour
urine protein of 6.3 g/d; albumin, 3.1 g/dL; creatinine, 1.2
mg/dL; and severe peripheral edema. Urine protein electro-
phoresis revealed mainly albumin. A renal biopsy was per-
formed.
Biopsy Findings
On light microscopic examination, there was a single core
of renal cortex containing 16 glomeruli, none of which was
globally sclerotic. Six glomeruli displayed lesions of collaps-
ing focal segmental glomerulosclerosis (FSGS) character-
ized by marked wrinkling and retraction of the glomerular
basement membrane and prominent hypertrophy and hyper-
plasia of overlying visceral epithelial cells, which contained
protein resorption droplets (Fig 1). The remaining 10 glo-
meruli appeared histologically unremarkable, although mild
swelling of visceral epithelial cells was noted. Proximal
tubules displayed protein droplets and diffuse degenerative
changes, including luminal ectasia, loss of brush border,
cytoplasmic attenuation with dropout of tubular epithelial
cells, and apoptotic figures. Focal tubular microcysts were
seen. There was mild-to-moderate tubular atrophy and inter-
stitial fibrosis involving approximately 30% of the cortex
sampled and associated with mild interstitial chronic inflam-
mation. Vessels displayed moderate arteriosclerosis.
Immunofluorescence was performed on formalin-fixed,
paraffin-embedded tissue after pronase digestion. Immuno-
fluorescence staining revealed low-intensity segmental tuft
staining for IgM in 3 of 12 glomeruli. Staining for IgG, IgA,
C3, C1q, ␬, ␭, fibrinogen, and albumin was negative in
glomeruli. The tissue fixed in glutaraldehyde for electron
microscopy contained medulla only. Therefore, electron
microscopy was not performed.
Pathologic Diagnosis
The pathologic findings were diagnostic of collapsing
FSGS. Collapsing FSGS is seen mainly in the setting of
human immunodeficiency virus (HIV)–associated nephropa-
thy or as a variant of idiopathic FSGS. We recently reported
the occurrence of collapsing FSGS in the setting of treat-
ment with high-dose pamidronate.1
Clinical Follow-Up
After the biopsy, treatment with pamidronate was discon-
tinued. Despite discontinuation of therapy, the patient’s
nephrotic syndrome progressively worsened, and 3 months
later in November 2000, she had a 24-hour urine protein of
NEPHROTIC SYNDROME FOLLOWING PAMIDRONATE
Fig 1. (A) A glomerulus displaying global collapse
of the glomerular tuft with marked podocyte swelling
and proliferation, forming a pseudocrescent. Podo-
cytes appear vacuolated and contain protein resorp-
tion droplets. (Periodic acid–Schiff, original magnifica-
tion ⴛ400.) (B) Another glomerulus with obliteration of
capillary lumina caused by global glomerular base-
ment membrane collapse. The hypercellularity in the
urinary space is attributable to podocyte proliferation,
as shown by the lack of continuity with the parietal
epithelium. (Jones methenamine silver, original magni-
fication ⴛ400.) (C) A low-power view shows wide-
spread tubular abnormalities, including microcyst for-
mation, luminal ectasia, and epithelial simplification.
(Periodic acid–Schiff, original magnification ⴛ125.)
1119
28.7 g/d; albumin, 2.6 g/dL; and creatinine, 2.8 mg/dL. At
that point, her renal function spontaneously began to im-
prove, and by March 2001, she had a 24-hour urine protein
of 3.4 g/day and creatinine of 2.0 mg/dL. Because of her
severe, life-threatening thoracic and lumbar spinal disease,
the difficult decision was made to restart treatment with
pamidronate. The patient received pamidronate, 90 mg intra-
venously, in late March and again in April; by May, her
24-hour urine protein had increased to 6.4 g/d. Shortly
thereafter, pamidronate therapy was discontinued, and the
patient began treatment with an alternative bisphosphonate.
DISCUSSION
Collapsing FSGS is a distinct variant of FSGS
characterized by marked wrinkling and collapse
of glomerular basement membranes and hypertro-
phy and hyperplasia of overlying podocytes.2,3
Collapsing FSGS first was reported in patients
with HIV-associated nephropathy,4 but it also
can be seen as a variant of idiopathic FSGS.2,3 In
both cases, collapsing FSGS most commonly
afflicts young black patients presenting with ne-
phrotic syndrome and renal insufficiency.2-5 Clini-
cally the collapsing variant of FSGS is distin-
guished from other variants of FSGS by the
presence of more severe nephrotic syndrome,
greater resistance to immunosuppressive therapy,
and a more accelerated course to renal failure.2,3,5
Evidence suggests that the pathogenesis of col-
lapsing FSGS involves primary injury to the
podocyte, with resultant altered cell cycle regula-
tion and reversion to an immature cellular pheno-
type.6
We reported the novel association of collaps-
ing FSGS and treatment with a therapeutic agent,
pamidronate.1 This conclusion was based on the
clinical findings in seven patients who developed
collapsing FSGS after treatment with high-dose
pamidronate and from data drawn from previous
animal studies.
The demographic profile of the seven patients
with pamidronate-associated collapsing FSGS
was unique in that all seven patients were older,
white, HIV-negative, and developed collapsing
FSGS in the course of active treatment for malig-
nancy.1 The cohort consisted of five women and
two men, with a mean age of 62.7 years (range,
49 to 77 years). All patients had a history of
malignancy (multiple myeloma in six and meta-
static breast carcinoma in one), and all were
treated with pamidronate for 15 to 48 months
before renal biopsy. Pamidronate therapy was
initiated at or below the recommended dose of 90
1120
mg intravenously monthly,10,11 but in five of the
seven patients the dose subsequently was in-
creased to 180 mg monthly (two patients) or 360
mg monthly (three patients). No patient had a
serum creatinine greater than 1.2 mg/dL before
the institution of pamidronate, and all developed
renal insufficiency (mean creatinine, 3.6 mg/dL;
range, 1.6 to 5.0 mg/dL) and nephrotic syndrome
during continuous monthly intravenous pamid-
ronate therapy. Patients had a mean 24-hour
urine protein of 12.4 g/d (range, 5.4 to 26 g/d),
and all were hypoalbuminemic and had periph-
eral edema.
Renal biopsy findings in all seven patients
with pamidronate-associated renal disease in-
cluded collapsing FSGS and severe tubular de-
generative changes, in some cases associated
with tubular microcyst formation.1 By electron
microscopy, podocytes displayed diffuse loss of
their highly differentiated cytoarchitecture, in-
cluding disappearance of primary processes and
extensive foot process effacement. In all seven
cases, there was no evidence of amyloidosis,
myeloma cast nephropathy, light chain deposi-
tion disease, or other form of multiple myeloma–
associated nephropathy and no changes of radia-
tion-associated or chemotherapy-associated
thrombotic microangiopathy or urate nephropa-
thy (tumor lysis syndrome).
Pamidronate disodium, a member of the
bisphosphonate class of drugs, is an inhibitor of
bone resorption that acts by direct binding to
calcium phosphate crystals within bone matrix,
leading to inhibition of osteoclastic activity. Es-
tablished indications for use of pamidronate in-
clude hypercalcemia, Paget’s disease, and osteo-
lytic metastases.7 The efficacy of pamidronate in
reducing skeletal complications in patients with
multiple myeloma or metastatic breast cancer is
well established.8-10
The causal relationship between high-dose
pamidronate and collapsing FSGS is based on
multiple lines of evidence. First, infrequent renal
toxicity has been seen with this agent.9-11 In one
study, 4 of 198 patients with multiple myeloma
(2%) were removed from a clinical trial because
of worsening renal insufficiency, although renal
biopsy findings were not reported.10 Second,
dosing in humans (0.4 to 1.5 mg/kg IV monthly;
maximum, 90 mg) is based in part on studies in
rats showing no nephrotoxicity at comparable
MARKOWITZ ET AL
levels.12 Dose-dependent nephrotoxicity is ob-
served in rats given higher doses (5.0 to 50
mg/kg).12 No long-term studies assessing renal
toxicity at doses greater than 90 mg intrave-
nously monthly have been reported in humans.
The clinical profile of the seven patients also
suggested strongly that high-dose pamidronate is
a causative agent in collapsing FSGS.1 The co-
hort consisted of predominantly older and exclu-
sively white individuals, all with a history of
malignancy and sharply contrasted with the pre-
dominantly young black population in whom
idiopathic collapsing FSGS typically is seen. The
development of proteinuria and renal insuffi-
ciency closely paralleled the administration of
pamidronate in escalating doses that exceeded
recommended levels. All seven patients had nor-
mal renal function before the start of pamidr-
onate therapy. Renal insufficiency and nephrotic
syndrome did not develop until the dosage was
increased to 180 mg/month in two patients and to
360 mg/month in three patients. The drug was
discontinued after biopsy in three patients, of
whom two had a mild decline in serum creatinine
over 3 and 5 months of follow-up.
Similar to idiopathic collapsing FSGS and
HIV-associated nephropathy,5 collapsing FSGS
associated with high-dose pamidronate is charac-
terized by an increased podocytic proliferation
index and reduced expression of synaptopodin,
both of which support a mechanism of direct
podocyte toxicity.1 The mechanism of renal epi-
thelial toxicity may involve cellular effects simi-
lar to those documented in the osteoclast.
Bisphosphonates are believed to inhibit bone
resorption by way of multiple mechanisms. First,
they mimic the calcium-chelating property of
inorganic pyrophosphate and inhibit bone disso-
lution.13 Second, bisphosphonates are internal-
ized by the osteoclast and inhibit the intracellular
mevalonate pathway required for the post-
translational lipid modification (ie, prenylation)
of guanosine triphosphatases (GTPases).14 This
activity disrupts anchoring of GTPases in cell
membranes, a requirement for subcellular com-
partmentalization and function of GTPases in
integrin signaling, endosomal trafficking, mem-
brane ruffling, and apoptosis.13,15-18 Bisphospho-
nates can disrupt the osteoclast cytoskeleton by
inhibiting the assembly of actin rings, leading to
loss of the osteoclast ruffled border.19 Similari-
NEPHROTIC SYNDROME FOLLOWING PAMIDRONATE
ties between the cytoskeleton and intracellular
processes in the osteoclast and the podocyte and
the high levels of bisphosphonates attained in
bone and kidney may explain the organ- and
cell-specific toxicities observed.
Establishing causality between a therapeutic
agent and a disease entity is a rigorous process.
Since the time of publication of collapsing FSGS
after treatment with high-dose pamidronate,1 we
have seen 10 additional cases, including one with
coexistent myeloma cast nephropathy, another
with coexistent vascular amyloidosis, and the
one reported herein. Although it is often impos-
sible to demonstrate, the ultimate proof of causal-
ity is to show that a disease occurs when a drug is
used, remits when the drug is discontinued, and
recurs after rechallenge with the same therapeu-
tic agent. For this reason, the case reported
herein is of particular importance in that the
development of nephrotic syndrome and the sub-
sequent fluctuations in proteinuria closely paral-
leled the use of pamidronate and the subsequent
discontinuation and reintroduction of this thera-
peutic agent.
Pamidronate is a widely used and important
therapeutic agent in the treatment of hypercalce-
mia of malignancy and osteolytic metastases.
Large-scale, long-term studies have not yet estab-
lished the safety of this agent when used at doses
that exceed recommended levels. At a minimum,
clinicians should assess periodically for protein-
uria and renal insufficiency in an effort to moni-
tor for nephrotoxicity. High-dose pamidronate
seems to be the first drug-induced form of collaps-
ing FSGS and joins interferon alfa and lithium
in causing potential drug-induced forms of
FSGS.20,21 In patients with multiple myeloma
and nephrotic syndrome, particularly patients
with minimal-to-absent monoclonal gammopa-
thy, the differential diagnosis should now include
collapsing FSGS after treatment with high-dose
pamidronate.
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