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Light chain crystalline kidney disease: Diagnostic urine microscopy as the

"liquid kidney biopsy"

Article  in  Clinical Nephrology · October 2014

DOI: 10.5414/CN108424 · Source: PubMed

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Neph
Education
©2014 Dustri-Verlag Dr. K. Feistle
ISSN 0301-0430
DOI 10.5414/CN108424
e-pub: ■■month ■■day, ■■year
Key words
light chain cast
nephropathy – acute
kidney injury – crystal
casts – multiple
myeloma
Received
July 10, 2014;
accepted in revised form
September 5, 2014
Correspondence to
Mark A. Perazella, MD
Professor of Medicine
Section of Nephrology,
Yale University School
of Medicine, 114 BB,
330 Cedar Street, New
Haven, CT 06520, USA
mark.perazella@yale.edu
Clinical Nephrology, Vol. ■■ – No. ■■/2014 (1-5)
Light chain crystalline kidney disease:
diagnostic urine microscopy as the “liquid
kidney biopsy”
Randy L. Luciano1, Ekaterina Castano2, Giovanni B. Fogazzi3,
and Mark A. Perazella1
1Sectionof Nephrology, 2Department of Pathology, Yale University School of
Medicine, New Haven, CT, USA, and 3Milano State University, Milano, Italy
Abstract. Multiple myeloma (MM) is
a plasma cell disorder, which often causes
parenchymal kidney disease. Light chain
(LC) cast nephropathy represents the most
common renal lesion. In some instances,
LC crystals precipitate within renal tubular
lumens and deposit within proximal tubular
cell cytoplasms. Importantly, urine micros-
copy in such patients can provide insight into
the underlying LC-related lesion. Here we
present two patients with MM complicated
by acute kidney injury (AKI) where LC crys-
talline casts were observed on urinary sedi-
ment analysis. Kidney biopsy revealed acute
tubular injury with LC crystal casts within
both tubular lumens and renal tubular epithe-
lial cell cytoplasms. These findings suggest
that the urinary sediment may be a non-inva-
sive way to diagnose LC crystalline-induced
AKI in patients with MM.
Introduction
Multiple myeloma (MM) is a malignant
plasma cell disorder that comprises ~ 1%
of all cancers [1]. Malignant plasma cells
produce abnormal paraproteins associated
with kidney disease in upwards of 40% of
patients [2, 3]. Acute kidney injury (AKI) as-
sociated with myeloma can be due to a num-
ber of parenchymal lesions; however, light-
chain (LC) cast nephropathy, LC deposition
disease, and AL amyloidosis are the most
common [4]. Urine protein-immunoelectro-
phoresis and automated urinalysis are com-
monly utilized to assess kidney involvement
in patients. However, these tests are unable
to provide insight into the specific kidney le-
sion. In contrast, urine sediment examination
may demonstrate findings reflective of the
underlying kidney lesion.
Myeloma LC cast nephropathy is the
most common kidney injury associated with
• 108424Luciano / 23. September 2014, 3:27 PM
MM [5]. The excessive light chain burden
leads to increased luminal concentration of
free LCs that aggregate with Tamm-Horsfall
protein leading to cast formation resulting in
obstruction and inflammation [6]. Interest-
ingly, monoclonal LC crystals can be seen
on biopsy specimens from MM patients with
AKI. However, these crystals have not been
described in the urine of patients. Here we
present two patients with LC crystalline casts
visualized in the urine sediment and con-
firmed with biopsy. Identification of these
crystalline casts in the urine can be a non-
invasive way of recognizing LC-associated
kidney injury such as cast nephropathy and
perhaps light chain proximal tubulopathy.
Case 1
A 48-year-old male with IgA-λ myeloma
of 3 years duration presented with AKI. His
treatment regimen included bortezomib, le-
nalidomide, and dexamethasone, resulting
in remission for 1 year, followed by dexa-
methasone, cyclophosphamide, and carfilzo-
mib upon recurrence. The patient was seen
3 months earlier at an outside hospital for an
increased serum creatinine (2.7 mg/dL). The
patient underwent kidney biopsy (described
below), received intravenous fluids, and
was continued on his chemotherapy regi-
men. Serum creatinine fluctuated between
2.0 – 2.6 mg/dL with serum and urine free
λ-LCs remaining elevated (700 – 900 mg/dL;
750 – 1,000 mg/dL). At the time of consul-
tation at our hospital, the patient was being
treated with vancomycin and piperacillin/
tazobactam for pneumonia with bacteremia.
His last dose of chemotherapy had been 1
week prior to admission. On review of his
Luciano, Castano, Fogazzi, and Perazella 2
Figure 1.  A, B: Light microscopy of spun urine
sediment for case 1 showing casts containing
amorphous crystalline structures (magnifica-
tion ×400); C, D: Light microscopy of spun urine
sediment for case 2 showing light chain crystalline
casts (magnification ×400).
hospital course his blood pressure had always
been normal (120 – 140/50 – 70 mmHg) and
his urine output non-oliguric. Exam was re-
markable for rales at his left lung base, but
otherwise no signs of volume depletion or
overload. Laboratory evaluations showed
serum sodium of 136  mEq/L, potassium of
5.2  mEq/L, chloride of 104  mEq/L, bicar-
bonate of 16.5 mEq/L, glucose of 84 mg/dL,
serum calcium of 8.5 mg/dL, BUN of 44 mg/
dL, and serum creatinine that had increased
from a baseline of 2.2 mg/dL to 3.6 mg/dL,
in 1 week. Serum free λ-LCs were 989 mg/
dL and urine free λ-LCs were 1,050 mg/dL,
while κ-LCs were suppressed. Urinalysis re-
vealed a specific gravity of 1.009, pH of 7, 2+
protein, negative glucose, 3 WBCs/hpf, and
1 RBC/hpf. Direct microscopic visualization
of the sediment demonstrated 1 – 2 renal tu-
bular epithelial cells/hpf, 3 – 5 free crystals
of varying shape/hpf, and 1 – 2 crystalline
casts/hpf (Figure 1A, B). The casts contained
irregularly shaped crystalline structures with
0 – 25% birefringence under polarized mi-
croscopy. The crystalline casts persisted with
repeat sediment evaluation. In the setting of
rising serum creatinine and serum free LCs,
treatment with cyclophosphamide, etopo-
side, and dexamethasone was started. Serum
• 108424Luciano / 23. September 2014, 3:27 PM
creatinine slowly improved to 1.5 mg/dL, se-
rum free LCs decreased, and the crystalline
casts decreased in density and subsequently
disappeared with subsequent urine sediment
evaluations.
Evaluation of a renal biopsy performed
for an elevated serum creatinine (see above)
at another institution from 3 months prior
revealed crystalline cast structures in tubu-
lar lumens (Figure 2A, B). Proximal tubules
showed acute injury with vacuolization,
blebbing, and dilatation. In addition, the in-
terstitium demonstrated a dense lymphoplas-
macytic infiltrate. Electron microscopy dem-
onstrated occasional hexagonal crystals in
tubular epithelial cells (images not shown).
Case 2
A 56-year-old gentleman with a 2-year
history of IgG-κ myeloma presented with
AKI. The patient had suffered a bout of AKI
that lead to kidney biopsy (see description
below). Treatment initially included bort-
ezomib and dexamethasone, which was as-
sociated with response and improved kidney
function. However, after 12 months, the
patient was switched to lenalidomide and
dexamethasone when the LC burden started
to increase and serum creatinine increased to
2.1 mg/dL. With this regimen, a reduction of
serum and urine free κ-LCs was noted and
kidney function improved to serum creati-
nine in the 1.5 – 1.8 mg/dL range. However,
the patient again became refractory to treat-
ment ~ 2 months prior to the current hospi-
talization, serum free LCs increased and he
was subsequently switched to carfilzomib
and dexamethasone. In this setting, the pa-
tient developed a rise in serum creatinine
from a baseline of 1.6  mg/dL to 3.2  mg/
dL over several weeks. Renal consultation
was commenced at this time. On evalua-
tion, the patient was mildly hypertensive
(140 – 170/60 – 90 mmHg) with no signs of
volume depletion. Laboratory evaluations
showed serum sodium of 135 mEq/L, potas-
sium of 3.8 mEq/L, chloride of 106 mEq/L,
bicarbonate of 19.7  mEq/L, glucose of
116  mg/dL, serum calcium of 9.1  mg/dL,
BUN of 49  mg/dL and serum creatinine of
3.2 mg/dL. Serum free κ-LCs were elevated
at 326  mg/dL and urine κ-LCs elevated at
AKI from light chain crystalline casts 3
Figure 2.  A, B: Biopsy specimen from case 1. Re-
fractile crystals are present within tubular lumens
surrounding proteinacious material. Examples of
crystalline material in periphery of tubule lumen are
indicated (black arrows). The tubules show acute tu-
bular injury with nuclear drop-out and flattening of the
epithelium (hematoxylin and eosin (H & E), original
magnification × 1,000); C, D: Biopsy specimen from
case 2. Tubular lumens show crystals, fractured light
chain casts, and fragments of sloughed-off epithelial
cells. Examples of crystal fragments within casts are
indicated (black arrows). Acute tubular injury is pres-
ent. Interstitium shows lymphocytic infiltrate (C: he-
matoxylin, phloxin, saffronin (HPS) stain; D: H & E,
both original magnification × 400).
Figure 3.  Electron microscopy shows numerous
crystalline structures within the cytoplasm of the tu-
bular epithelial cells (A: Electron microscopy, direct
magnification × 5,000) and in the tubular lumen (B:
Electron microscopy, direct magnification × 4,000).
239  mg/dL, while λ-LCs were suppressed.
Urinalysis revealed a specific gravity of
1.010, 1+ protein, negative glucose, and 8
• 108424Luciano / 23. September 2014, 3:27 PM
RBCs/hpf. Urine sediment analysis on two
separate occasions demonstrated aggregates
of crystals and crystalline casts, with 25%
birefringence with polarization (Figure 1C,
D). On repeat samples, separated by several
months LC crystalline casts persisted.
Evaluation of a renal biopsy performed
for AKI from 2 years prior confirmed the
presence of LC crystalline casts (Figure 2C,
D). The proximal tubules demonstrated ex-
tensive tubular injury. Tubular lumens were
filled with eosinophilic refractile material
of varying shapes. Many tubular profiles
showed light chain crystals in the cytoplasm
of the proximal tubular epithelial cells and
LC crystals in distal tubular lumens as well
as fractured casts with epithelioid reaction.
In addition there was a significant lym-
phocyte predominant interstitial infiltrate.
Electron microscopy revealed multifaceted
crystals in the proximal tubular lumens and
within the cytoplasm of tubular epithelial
cells (Figure 3).
Discussion
The two cases described are unique in
that they demonstrate free LC crystals and
LC crystalline casts in the urine sediment of
patients with multiple myeloma and LC-re-
lated kidney disease. These findings have not
been previously reported in the literature. In
addition, these findings reinforce that urine
microscopy can provide a window into the
underlying kidney lesion and that urine sedi-
ment findings can at times truly be the “liq-
uid kidney biopsy”.
Monoclonal LC crystal formation has
been previously reported in biopsy speci-
mens of the kidneys and other organs. Re-
ported cases of paraprotein-related crystal
deposition demonstrated both κ- and λ-LC
crystals deposited in kidney, heart, lung,
spleen, thyroid, skin, and intestine [7]. Re-
nal deposition of LC crystals has been asso-
ciated with both AKI and proximal tubular
dysfunction [8, 9, 10, 11]. While κ-LC crys-
tal deposition within the kidneys has been
more widely reported, λ-LC crystals have
also been noted. In some cases, LC crystal
deposition leads to rapidly progressive kid-
ney failure [9, 12].
Luciano, Castano, Fogazzi, and Perazella 4
Fogazzi et al. [13] utilized immuno-
fluorescence (IF) staining (anti-sera to LC
immunoglobulins) of the urine sediment to
identify monoclonal LCs in patients with
kidney disease and various monoclonal gam-
mopathies. They described urinary casts
and other various shaped particles in the
urine of 20 out of 27 patients with monoclo-
nal disease and none in 25 control patients
with non-monoclonal kidney disease. The
sensitivity of the urine sediment IF staining
was 74%, the specificity was 100%, and the
positive predictive value was 100%. Another
case of myeloma cast nephropathy described
“hexagonal crystals” in the urine (not photo-
graphed) that were similar to those seen in
the kidney biopsy light and electron micros-
copy specimens [14]. While neither of these
cases showed images of LC crystalline casts
in the urine sediment, these data confirm that
urine sediment contains identifiable LC both
free and within casts. Our data suggest that
urine microscopy can identify LC crystals
in the urine sediment, which can provide a
window into the process within the renal pa-
renchyma.
The major challenge for the urine mi-
croscopist is to distinguish these LC crystal-
line casts from other urinary casts, such as
coarsely granular casts. Careful inspection
of the crystalline casts reveals the following
unique characteristics when compared with
granular casts. First, these casts contain crys-
tals that are also seen free in the urine of both
cases. In addition, these crystals were up to
25% birefringent under polarization, which
is not seen with granular casts. Finally, the
crystalline casts have a refractile appearance
that is not seen with granular casts.
Urine microscopy is a crucial part of the
evaluation of kidney disease, including those
with AKI, hematuria, and proteinuria [15].
Thorough evaluation of the spun urinary sed-
iment provides data that cannot be otherwise
obtained by dipstick urinalysis and automat-
ed or laboratory technician-performed urine
examination. Expert differentiation of uri-
nary cell morphology, accurate identification
of cellular and non-cellular casts, and recog-
nition and diagnosis of various endogenous
and drug-related crystals can lead to rapid
diagnosis of the kidney-related process.
Paraprotein-related diseases such as MM
and associated monoclonal LC disorders,
• 108424Luciano / 23. September 2014, 3:27 PM
which are commonly complicated by kidney
injury, lend themselves well to diagnostic
evaluation by urine sediment examination.
While serum and urine protein immunoelec-
trophoresis and serum free LCs are routinely
utilized to assess for kidney involvement,
they cannot distinguish the type of lesion
present. Nowadays, clinicians utilize the au-
tomated urinalysis report to confirm potential
renal disease while rarely viewing the urine
sediment. As a result, the renal diagnosis is
presumed based on serum and urine immu-
noglobulin (Ig) or LC testing combined with
urinalysis. A percutaneous kidney biopsy is
pursued for diagnostic adjudication and con-
firmation in some cases.
In conclusion, we report unique urinary
LC crystalline casts and free crystals in two
patients with MM. Thorough examination of
the urine sediment in patients with monoclo-
nal LCs and evidence of kidney disease will
potentially provide the diagnosis. It is logical
that patients with monoclonal diseases and
evidence for kidney injury should have urine
microscopy performed by an appropriately
trained nephrologist. In addition, it is possi-
ble that urine sediment exam in patients with
an underlying monoclonal gammopathy may
provide information about kidney injury and
serve as a biomarker of early kidney disease.
Conflicts of interest
None.
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