Reversal of Dialysis-Dependent Renal Failure in Light-Chain
Deposition Disease by Autologous Peripheral Blood
Stem Cell Transplantation
Frank Firkin, MB, BS, Prudence A. Hill, MB, BS, Karen Dwyer, MB, BS, and Hilton Gock, MB, BS
● Specific treatment of light-chain deposition disease has been reported as ineffective in altering the course of the
severe or end-stage renal failure it causes. The authors describe a case of biopsy-proven primary light-chain
deposition disease of the kidney, severe renal failure, and incipient dialysis dependency, treated by autologous
peripheral blood stem cell transplantation, that led to reversal of dialysis dependency and sustained improvement
in renal function. Am J Kidney Dis 44:551-555.
© 2004 by the National Kidney Foundation, Inc.
INDEX WORDS: Light-chain deposition disease (LCDD); autologous peripheral blood stem cell transplantation;
renal failure.
L
IGHT-CHAIN deposition disease (LCDD) is
characterized by organ damage owing to
toxic effects of granular aggregates of abnormal
monoclonal light chains produced by a clonal
plasma cell disorder.1 LCDD can occur either as
a primary monoclonal disorder unaccompanied
by features of multiple myeloma, or in association with deposition of heavy chains, or in association with multiple myeloma.2 Renal impairment is the most common clinically significant
complication, occurring in 52% to 70% of patients3,4 and usually progresses to end-stage renal failure. The rate of progression varies considerably, and although the disorder is usually fatal,
median survival time from diagnosis is considerably longer5 than that in light-chain amyloidosis,6 where organ damage is caused by deposition of fibrils consisting of abnormal light chains.7
Although orally administered chemotherapy in
LCDD with early renal failure may alter renal
prognosis, the duration of response usually is
limited.5 In addition, severe renal failure and
dialysis dependency is generally considered irreversible.5 We report a case of primary LCDD
with rapid progression of renal failure to the
point of dialysis dependency, where autologous
peripheral blood stem cell transplantation after
myeloablative treatment with melphalan resulted
in significant and sustained recovery of renal
function.
CASE REPORT
Presentation
A 55-year-old white man with a 2-year history of hypertension presented with acute pulmonary edema without elevation of cardiac enzymes and promptly responded to medical
therapy. Examination found mild cardiomegaly with apex
beat displacement 2 cm laterally and mild hepatomegaly
with a liver span of 14 cm. The serum creatinine level was
2.15 mg/dL (190 ␮mol/L; normal range, 0.79 to 1.24 mg/dL
[70 to110 ␮mol/L]).
Investigations
His serum total protein level was 5.4 g/dL (54 g/L; normal
range, 6.0 to 8.0 g/dL [60 to 80 g/L]); albumin, 3.1 g/dL (31
g/L; normal range, 3.5 to 5.0 g/dL [35 to 50 g/L]); alkaline
phosphatase, 230 U/L (normal range, 30 to 110 U/L); gamma
glutamyl transferase, 140 U/L (normal range, 7 to 43 U/L);
aspartate transaminase, 83 U/L (normal, ⬍55 U/L); and
bilirubin, 0.5 mg/dL (9 ␮mol/L; normal, ⬍1.3 mg/dL [⬍22
␮mol/L]). Monoclonal protein was not detected on serum
protein electrophoresis. The serum immunoglobulin G, immunoglobulin A, and immunoglobulin M levels were 0.51
g/dL (normal range, 0.7 to 1.6), 0.06 g/dL (normal range,
0.07 to 0.4), and 0.04 g/dL (normal range, 0.04 to 0.23),
respectively. The hematocrit level was 0.33 (normal range,
0.40 to 0.54), and the mean cell volume 86 fL (normal, 80 to
98). White cell count, differential, and platelet counts were
normal. Urinary protein excretion was 0.65 g/d (⬍0.08), and
creatinine clearance was 39 mL/min (0.65 mL/s; normal
range, 90 to 150 mL/min [1.50 to 2.50 mL/s]). Urine protein
electrophoresis showed nonselective glomerular proteinuria,
and a small monoclonal ␬ chain band on immunofixation of
approximately 0.005 g/dL. Urine microscopy results were
unremarkable. Skeletal x-ray examination was normal. Trans-
From the Departments of Clinical Hematology and Medicine, University of Melbourne, Melbourne; and the Departments of Anatomical Pathology and Nephrology, St Vincent’s Hospital, Fitzroy, Victoria, Australia.
Received February 13, 2004; accepted in revised form
May 3, 2004.
Address reprint requests to Dr. Hilton Gock, Physician
In-Charge of Dialysis, Department of Nephrology, St Vincent’s Hospital, PO Box 2900, Fitzroy VIC 3065, Australia.Email: [email protected]
© 2004 by the National Kidney Foundation, Inc.
0272-6386/04/4403-0018$30.00/0
doi:10.1053/j.ajkd.2004.05.031
American Journal of Kidney Diseases, Vol 44, No 3 (September), 2004: pp 551-555
551
552
FIRKIN ET AL
.
Fig 1. (A) Nodular expansion of glomerular mesangium by PAS-positive material in initial renal biopsy
(original magnification ⴛ250).
(B) Nodular mesangial, linear
glomerular peripheral wall,
and linear tubular basement
membrane positivity with direct immunofluorescent staining for ␬ light chains in initial
renal biopsy (original magnification ⴛ100). (C) Abundant
granular electron-dense aggregates indicated by arrows
on external aspect of the basement membrane adjacent to a
tubular epithelial cell (T) in
initial renal biopsy (original
magnification ⴛ17,500). (D)
Marked nodular expansion of
glomerular mesangium by
PAS-positive material in second renal biopsy 7 months
postautograft. Note increased
tubulointerstitial damage compared with initial biopsy (original magnification ⴛ250)
esophageal ultrasound scan showed mild left ventricular
hypertrophy; mild left ventricular dilatation with some global
impairment, and an ejection fraction of 40%. Ultrasound
scan showed normal-size kidneys with diffusely increased
cortical echogenicity. Technetium-radiolabelled mercapto
acetyl triglyceride nuclear scanning showed a moderate
bilateral, diffuse, reduction in renal uptake, and moderate-tosevere bilateral, diffuse, reduction in secretion. No renal
artery stenosis was seen on magnetic resonance angiography.
Renal biopsy results showed all glomeruli had some
nodular mesangial expansion by periodic acid–Schiff (PAS)–
positive material (Fig 1A). There was focal nodular hyalinosis, mild thickening of arteriolar walls, and patchy mild
interstitial fibrosis with focal tubular atrophy. Congo red
stain was negative. Immunofluorescence studies found strong
staining for ␬ light chains in glomerular mesangium and
peripheral capillary walls together with linear peritubular
staining (Fig 1B). Staining for ␭ light chains was negative.
Electron microscopy results showed punctate granular electron-dense deposits in the expanded mesangial matrix, subendothelial aspect of the glomerular basement membrane,
basement membrane of blood vessel walls, and outer aspect
of the tubular basement membrane (Fig 1C) consistent with
LCDD. Liver biopsy results showed preserved lobular architecture, no significant abnormality of hepatocytes or Kupffer
cells, and mild expansion of portal tracts with an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils.
Arteriolar walls in portal tracts were PAS positive, and
Congo red negative. Inadvertent use of an unsuitable fixative
made it impossible to perform immunofluorescent and electron microscopic assessment of light-chain deposition in the
liver biopsy material, and the patient declined a further liver
biopsy. The histochemical appearance of involvement of
arterioles in the liver biopsy with PAS-positive material was
identical to that in arterioles in the renal biopsy, where the
PAS-positive material was shown to correspond to deposition of ␬ light chains, providing presumptive evidence of
STEM CELL AUTOGRAFT FOR LIGHT-CHAIN NEPHROPATHY
Table 1.
553
Course of Biochemical and Cardiac Function Parameters
Time in Relation to Autograft
Serum creatinine (⬍1.24 mg/dL)
Creatinine clearance (⬎90 mL/min)
Urine protein excretion (⬍ 0.08 g/d)
Urine ␬ light chain
Cardiac ejection fraction (⬎50%)
Serum alkaline phosphatase (⬍110 U/L)
Serum albumin (3.5 to 5.0 g/dL)
Hemoglobin (13.0 to 18.5 g/dL)
⫺2 mo
⫺1 wk
⫹3 mo
⫹28 mo
⫹43 mo
2.04
39
0.65
Detected
40%
230 U/L
3.1 g/dL
10.5 g/dL
6.67
19
2.13
—
35%
423 U/L
3.1 g/dL
9.0 g/dL
3.17
13
0.75
Trace
—
159 U/L
4.3 g/dL
14.9 g/dL
2.38
37
0.15
Not detected
51%
134 U/L
4.1 g/dL
14.2 g/dL
2.49
—
—
Not detected
—
—
4.2 g/dL
14.7 g/dL
NOTE. To convert creatinine in mg/dL to ␮mol/L, multiply by 88.4; creatinine clearance in mL/min to mL/s, multiply by
0.01667; serum albumin and hemoglobin in g/dL to g/L, multiply by 10.
hepatic ␬ light-chain deposition. The bone marrow aspirate
was normocellular with a normal differential. Plasma cell
numbers (5%) were not increased, although rare morphologically abnormal forms were noted. An attempt to assess
plasma cell clonality by flow cytometric evaluation of cytoplasmic immunoglobulin light-chain specificity was unsuccessful because insufficient plasma cells were present for
analysis. The trephine biopsy results showed normocellular
bone marrow containing several small aggregates of morphologically normal mature lymphoid cells and scattered small
collections of plasma cells in numbers within the normal
range. Gastric and small bowel biopsy results showed normal mucosa and were PAS and Congo red negative.
Progress
Despite control of hypertension with angiotensin-converting enzyme inhibition, the patient had significant fluid retention, with symptoms and signs of biventricular heart failure,
and required increasing doses of diuretics over the next 2
months. The course of renal, cardiac, and hepatic parameters
shown in Table 1 indicates the significant deterioration in
renal function, increase in urinary protein loss, and decline
in cardiac ejection fraction. The patient was transfused with
packed red cells and recombinant erythropoietin commenced because the hemoglobin level fell to 9.5 g/dL (95
g/L), presumably a consequence of renal failure.
Because LCDD was considered the cause of the relatively
rapid progression of organ damage, specific treatment by
autologous peripheral blood stem cell transplantation using
a myeloablative dose of melphalan was undertaken. A filgrastim mobilized peripheral blood stem cell (PBSC) collection
was performed without incident. Melphalan, 100 mg/kg,
was administered intravenously on 2 successive days followed by infusion of PBSC (6.5 ⫻ 106 CD 34⫹ cells/kg
body weight) 48 hours after the second dose of melphalan,
as described by Tricot et al8 for autologous PBSC transplantation in myeloma patients with renal impairment.
Hemodialysis was commenced 1 day post-PBSC infusion
because of fluid retention precipitating heart failure, hyperkalemia, and persistent nausea and vomiting from uremia
with progression of the serum creatinine level to 7.35 mg/dL
(650 ␮mol/L). Daily hemodialysis was performed with good
effect but was suspended after 4 treatments for the next 6
days after development of the expected profound neutropenia, because of concerns of further reducing availability of
neutrophils by removal from blood passing through the
hemodialysis apparatus. During this time, the serum creatinine level increased to 8.10 mg/dL (720 ␮mol/L), progressive fluid retention developed, and a septic episode required
antibiotic treatment and recommencement of hemodialysis
for uremic symptoms and cardiac failure. Neutrophil recovery commenced 11 days post-PBSC infusion and was complete within 3 weeks.
Renal function gradually recovered, with dialysis performed thrice weekly for 1 week and twice weekly for the
following week, then ceased. The reversal of deteriorating
renal function postautograft is illustrated by the course of the
plasma creatinine in Fig 2. ACE inhibition was continued
throughout. Kappa light chains were detectable in urine by
immunofixation at a concentration of ⬍0.001 g/dL 3 months
postautograft, after which they were undetectable. Despite
the reduction in creatinine level and urine protein loss
postautograft, results of renal biopsy performed 7 months
postautograft showed no obvious reduction in the extent of
immunofluorescent staining for ␬ light chains or PASpositive material at that time compared with the biopsy
performed 11 weeks before the autograft, as shown in Fig
1D by persistence of extensive infiltration of glomerular
mesangium by PAS-positive material. It also showed increased interstitial fibrosis and tubular atrophy compared
with the biopsy performed before the relatively rapid renal
function deterioration in the 2 months before the autograft,
consistent with sequelae of substantial permanent renal
parenchymal damage.
The subsequent clinical course, as illustrated in Table 1,
was marked by a progressive fall in serum creatinine level to
a plateau 28 months postautograft, which was sustained
between 2.26 and 2.83 mg/dL (200 to 250 ␮mol/L) for the
subsequent 25 months. Creatinine clearance remained severely depressed at 14 mL/min (0.23 mL/s) 3 months postautograft and 13 mL/min (0.22 mL/s) at 5 months but improved to 44 mL/min (0.73 mL/s) at 20 months, after which
it remained essentially unchanged. Daily urine protein excretion progressively decreased to a nadir slightly above the
554
FIRKIN ET AL
Fig 2. Course of renal
function indicated by rising
plasma creatinine level and
introduction of hemodialysis dependency over a period of 12 weeks followed by
substantial partial recovery
after myeloablative melphalan treatment followed by autologous peripheral blood
stem cell rescue. To convert
creatinine in mg/dL to
␮mol/L, multiply by 88.4.
upper normal limit 28 months postautograft, after which the
value remained unchanged. Hypertension became less severe, and was controlled with low-dose perindopril. The
hematocrit level rose and remained at normal levels after
suspension of erythropoietin 3 months postautograft. Liver
size and function tests also normalized, and the cardiac
ejection fraction 28 months postautograft recovered to the
lower limit of normal. The patient resumed normal activities
and has declined further renal biopsy.
DISCUSSION
The current report describes sustained improvement of disordered renal, cardiac, and hepatic
function in a patient with primary ␬ LCDD after
autologous PBSC transplantation with high-dose
melphalan. Because the observed period of pancytopenia was not prolonged and was followed
by prompt hemopoietic recovery postautograft,
we have shown that undue high-dose melphalan
myelotoxicity reported in myeloma patients with
renal failure after autografting8 can be avoided
by a period of intense daily dialysis to allow
temporary suspension for a time when profoundly neutropenic. The suspension of hemodialysis for 6 days suggested that the patient had
some residual renal function; however, it could
not be sustained because of worsening uremia
and fluid retention combined with his catabolic
state. Thus, the renal failure was severe and
either very near or at end stage before the response to therapy, suggesting recovery of at least
some viable residual renal tissue from disease.
Previous reports have suggested that specific
treatment for LCDD did not alter the course of
severe renal failure particularly when the plasma
creatinine level has reached higher than 4 mg/dL
(352 ␮mol/L).5
The rate of deterioration of renal function in
primary LCDD has been reported to vary considerably from patient to patient, and the median
time to fatal outcome is substantially longer5
than the 13.2 months reported for light-chain
amyloidosis,6 in which light-chain deposition is
also the basis of organ failure. Treatment with
oral agents that cause regression of plasma cell
malignancy can stabilize or improve impaired
renal function in some patients,5 and there is 1
previous report of improvement in impaired cardiac function in a patient with the disorder.9
More intensive treatment, either as syngeneic
bone marrow transplantation in a patient with
primary LCDD10 or as autologous peripheral
blood stem cell transplantation in another patient
with myeloma and associated LCDD,11 has been
reported to produce stabilization or improvement
of renal and hepatic dysfunction, where the high
dose chemotherapy resulted in protracted suppression of the underlying clonal plasma cell disorder.
The decision to perform an autograft in our
patient was based on the premise that the rapid
deterioration of renal function was primarily
caused by light-chain–induced nephrotoxicity,
and that prompt and substantial reduction in
light-chain deposition was required to avert incipient end-stage renal failure. There is consider-
STEM CELL AUTOGRAFT FOR LIGHT-CHAIN NEPHROPATHY
able reported experience in the use of high-dose
chemotherapy with autologous stem cell rescue
for producing regression of organ damage in
light-chain amyloidosis in which an analogous
clonal plasma cell disorder is the basis of the
organ damage. Major regression of amyloidinduced organ damage and prolongation of survival occurs in approximately 60% of survivors
of high-dose melphalan autografts, but treatmentrelated mortality of almost 40% is very high and
is even higher in patients with renal or cardiac
failure. Such high peritransplant mortality is,
however, not a feature in patients with multiple
myeloma, including patients with substantial degrees of renal impairment8 sometimes associated
with deposition of light chains similar to that in
LCDD.9 The tolerance of stem cell harvesting
and transplant-related toxicity by our patient
who had evidence of some cardiac and hepatic
compromise as well as dialysis-dependent renal
failure, suggests that autograft treatment-related
mortality may be less in LCDD than in lightchain amyloidosis.
Improvement in renal function postautograft
was slow and incomplete. The natural history of
LCDD that has progressed to a requirement for
hemodialysis typically is associated with ongoing hemodialysis dependency, in contrast to the
substantial and protracted recovery of renal function that occurred in the current subject. A possible mechanism for the sustained recovery of
renal function is the reduction in generation of
nephrotoxic light chains as a consequence of
high-dose melphalan on the underlying plasma
cell disorder. A response of the underlying plasma
cell dyscrasia to high-dose melphalan was indicated by disappearance from the urine of the ␬
monoclonal protein detected at diagnosis, although the period was greater than 3 but less than
7 months. Such a slow rate of depression of
production presumably contributed to the persistence of ␬ chain deposits in the renal biopsy 7
months postautograft. Slow improvement in renal function, indicated by decrease in plasma
creatinine, and improvement in creatinine clearance continued for more than 12 months postautograft. This was accompanied by improvement
in cardiac ejection fraction and in restoration of
normal hepatic size and function tests, presum-
555
ably reflecting some resolution of light-chain
deposition-induced toxicity in these organs. Incomplete recovery of renal function correlated
with microscopically demonstrated development
of permanent glomerular and interstitial fibrotic
changes in the period after the initial renal biopsy. The current duration of treatment response
is 43 months. The clinical course and relatively
prolonged duration of benefit in this subject
provides evidence of therapeutic feasibility and
efficacy of a single treatment with high-dose
melphalan followed by autologous peripheral
blood stem cell transplantation for actively progressive LCDD.
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