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& 2011 International Society of Nephrology
see commentary on page 701
Myeloproliferative neoplasms cause glomerulopathy
Samar M. Said1, Nelson Leung2, Sanjeev Sethi1, Lynn D. Cornell1, Mary E. Fidler1, Joseph P. Grande1,
Sandra Herrmann2, Ayalew Tefferi3, Vivette D. D’Agati4 and Samih H. Nasr1
1
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA; 2Division of Nephrology and
Hypertension, Mayo Clinic, Rochester, Minnesota, USA; 3Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA and
4
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York, USA
Myeloproliferative neoplasms are clonal hematopoietic stem
cell disorders that can produce an undefined
glomerulopathy. To better characterize the glomerular
disease associated with myeloproliferative neoplasms, we
evaluated features of 11 patients with myeloproliferative
neoplasm-related glomerulopathy that included 8 patients
with primary myelofibrosis, and 1 each with chronic
myelogenous leukemia, polycythemia vera, and essential
thrombocythemia. Indications for biopsy were nephrotic-
range proteinuria (nephrotic syndrome in four) and chronic
renal insufficiency. The mean time from diagnosis of the
neoplasms to biopsy was 7.2 years. Histologically, mesangial
sclerosis and hypercellularity were seen in all 11 cases,
segmental sclerosis in 8, features of chronic thrombotic
microangiopathy in 9, and intracapillary hematopoietic cells
in 4. On follow-up, seven patients had persistent renal
dysfunction and four progressed to end-stage renal disease
(ESRD). Thus, glomerulopathy appears to be a late
complication of myeloproliferative neoplasms, particularly
primary myelofibrosis, with guarded prognosis. Greater
awareness of this entity and larger studies are needed to
define possible therapies.
Kidney International (2011) 80, 753–759; doi:10.1038/ki.2011.147;
published online 8 June 2011
KEYWORDS: glomerulopathy; glomerulosclerosis; pathology; proteinuria
Correspondence: Samih H. Nasr, Division of Anatomic Pathology, Hilton
10–20, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota 55905, USA.
E-mail: nasr.samih@mayo.edu
Received 7 February 2011; revised 12 March 2011; accepted 22 March
2011; published online 8 June 2011
Kidney International (2011) 80, 753–759
original article
Myeloproliferative neoplasms (MPNs, formerly called
chronic myeloproliferative disorders) are clonal hematopoi-
etic stem cell disorders characterized by expansion of one or
more of the myeloid lineages, including granulocytic,
erythroid, megakaryocytic, and mastocytic. MPN occurs
primarily in older adults. In the current 2008 World Health
Organization system, MPN are subclassified into eight
separate entities: chronic myelogenous leukemia (CML),
polycythemia vera (PV), essential thrombocythemia (ET),
primary myelofibrosis (PMF), systemic mastocytosis, chronic
eosinophilic leukemia not otherwise specified, chronic
neutrophilic leukemia, and unclassifiable MPN.1 The major
complications in MPN are transformation into acute myeloid
leukemia (seen particularly in CML) and thrombohemor-
rhagic events, which are most common in PV and ET.
Renal involvement by MPN is infrequent. In patients with
PMF, extramedullary hematopoiesis, which typically affects
the spleen and liver, rarely involves the perirenal tissue or
renal interstitium and may lead to obstructive uropathy and
renal failure.2 Acute renal failure may develop in patients
with ET because of bilateral thrombosis of renal arteries or
occlusion of the urinary tract by blood clots3,4 and in patients
with CML as a result of tumor lysis syndrome or leukemic
infiltration of the interstitium.5,6
Glomerular abnormalities have rarely been described in
patients with MPN with only a single small series reported in
the English literature.7 In this series from Hong Kong, Au
et al.7 reported five patients with MPN (two PV, two ET, and
one PMF) who developed proteinuria. Kidney biopsy
revealed focal segmental glomerulosclerosis (FSGS) and
mesangial sclerosis. Perazella et al.8 reported a patient with
PMF who developed a glomerulopathy characterized by
mesangial hypercellularity and sclerosis together with glo-
merular intracapillary infiltrating hematopoietic cells, with-
out immune deposits on immunofluorescence (IF).
Herein, we report a series of 11 patients with MPN,
including 8 with PMF, 1 with ET, 1 with PV, and 1 with CML,
who developed proteinuria and renal insufficiency. Kidney
biopsy showed a peculiar form of glomerulopathy, for which
we propose the term ‘MPN-related glomerulopathy,’ char-
acterized by a combination of mesangial sclerosis and
hypercellularity, segmental sclerosis, features of chronic
thrombotic microangiopathy (TMA), and intracapillary
753
original article SM Said et al.: Myeloproliferative neoplasm-related glomerulopathy

Abbreviations: Bx, biopsy; CML, chronic myelogenous leukemia; ESRD, end-stage renal disease; ET, essential thrombocythemia; F, female; F/U, follow-up; H, Hispanic; M, male; MMF, mycophenolate mofetil; MPN,
hematopoietic cell infiltration. In all cases, electron micro-

myeloproliferative neoplasms; NA, not available; PMF, primary myelofibrosis; PRD, persistent renal dysfunction; PV, polycythemia vera; S. albumin, serum albumin; Scr, serum creatinine; UA, urinalysis; W, white; WBC, white blood
PRD/death (Scr 4.6 mg/dl,

PRD/death (Scr 1.4 mg/dl,

proteinuria 300 mg/dl)
scopy (EM) and IF excluded immune complex-mediated

PRD (Scr 1 mg/dl, 4+

proteinuria 8.9 g/d)

proteinuria 1.6 g/d)

proteinuria 7.2 g/d)

PRD (Scr 2.8 mg/dl,
PRD (Scr 2.6 mg/dl,

proteinuria on UA)
PRD (Scr 2 mg/dl)
glomerulonephritis. Proper recognition of MPN-related

PRD (Scr 2 mg/dl,

protein on UA)
glomerulopathy and differentiation from other forms of

ESRD/death
Outcome
sclerosing glomerulopathy, TMA, and immune-complex

ESRD
ESRD
ESRD
glomerulonephritis are essential for diagnosis and manage-
ment of the renal disorder.

Duration Treatment

Benazepril

Lisonipril
Lisonipril

Losartan
of F/U in of renal

Steroids

Steroids
Steroids
months disease

None

None

None
MMF
RESULTS
Clinical features
The cohort consisted of eight men and three women with a

11

62

43
11

3
4

2
3

9
mean age of 73 years (range 60–87 years) at biopsy. In all, 10
patients were white and 1 was Hispanic. The type of MPN

to biopsy in years
diagnosis of MPN
was PMF in eight patients (#1–8), ET in one (#9), CML in

Time from
one (#10), and PV in one (#11). A history of leukocytosis was

3.5

5
1

9
4

8
3

7
17

15
present in 91% of cases (exception #5), and a history of
thrombocytosis was present in 82% (exceptions #2, 5).
Splenomegaly was a common finding, present in 73% of

Pomalidomide (thalidomide

Hydroxyurea, azothiaprine,
analog), blood transfusion

Anagrelide, erythropoietin
patients (exceptions #2, 4, 9). All eight patients with PMF

Hydroxyurea, anagrelide

Hydroxyurea, interferon,

Phlebotomy, anagrelide
(JAK 2 inhibitor), blood
Hydoxyurea, TG101348

splenectomy (after Bx)

(#1–8) had a leukoerythroblastic blood picture and anemia.

Hydroxyurea, blood

Blood transfusion,
Blood transfusion
The therapeutic modalities used to treat MPN are listed in

erythropoietin
Table 1. With the exception of interferon used in one patient,

transfusion

transfusion

Anagrelide
Therapies
for MPN

Gleevec
no patient received agents known to cause glomerular
nephrotoxicity. Eight patients had a history of hypertension,
Table 1 | Clinical data of patients with myeloproliferative neoplasms-related glomerulopathy

which was well controlled on anti-hypertensive medications.

count (K/ Peak WBC Type of

None of the patients were active smokers, but three had a

(K/mm3) MPN

CML
PMF

PMF

PMF

PMF

PMF

PMF
PMF
PMF

PV
ET
remote history of smoking, which had been discontinued
11–30 years before biopsy. Three patients had a history of
18.8

34.7
15.9
6.6
17

86

29

50

18

63

48
gout, and one had ocular pemphigoid.
The indications for renal biopsy were proteinuria
Peak platelet

mm3)

(43 g/day in all patients; mean 24 h urine protein 6.8 g, range

1100
507

231

606

314

814

600

676

713

984
NA
3–14 g) and chronic renal insufficiency (10 patients; mean
serum creatinine 2.5 mg/dl, range 1–5.6 mg/dl). Only four
(mg/dl)

patients (36%) had nephrotic syndrome. Hypoalbuminemia

Scr

2.2

2.3

5.6

1.6

4.6

1.5
3.4
1.3

2.5

2.2
1
was present in nine patients (82%); the mean serum albumin
was 3.0 g/dl (range 1.8–4.5). Peripheral edema was present in
syndrome
Nephrotic

six patients (55%). Microscopic hematuria was present in

three patients (27%; #1, 3, 10). Three patients (27%) had
Yes

Yes

Yes

Yes
No

No
No

No
No
No

No

leukocyturia (#3, 6, 10). One patient (#5) was started on

permanent dialysis for uremic symptoms 1 day after the kidney
Edema

biopsy. None of the six patients tested for serum complement

Yes

Yes

Yes

Yes

Yes

Yes
No
No

No
No
No

(C) had low C3 or C4 levels. Hepatitis C antibody and hepatitis

Proteinuria S. albumin

B antigen were negative in all seven patients tested.

(g/dl)

2.8

1.8
3.8

2.9
2.7

4.5

3.4

2.3
3

Anti-nuclear antibody was negative in all five patients tested.

Renal biopsies were generally performed late in the course
of the hematological disease. The mean time from diagnosis
(g/24)

11.8
3.2

3.4
3.6

3.2
13

14

of MPN to renal biopsy was 7.2 years (range 1–17 years),

whereas the mean time from discovery of proteinuria to renal
Age

biopsy, available in seven patients, was 24.1 months (range

64

87

82

73

78

67
72
60

74

78

68

0.5–84 months).
Race

Clinical follow-up was available in all 11 patients (Table 1).

W

W
W
W

W
H

The mean duration of follow-up for the entire cohort was

Patient Gender

14.4 months (range 2–62 months). No specific treatment was

M

M
M
M

M
F

cell count.

given for the renal disease in three patients, whereas four

patients were treated with renin–angiotensin system blockade
10

11
1

6
7
8

alone (angiotensin-converting enzyme inhibitor in three and

754 Kidney International (2011) 80, 753–759

SM Said et al.: Myeloproliferative neoplasm-related glomerulopathy original article

Table 2 | Pathological findings in myeloproliferative neoplasms-related glomerulopathy

% of % of Tubular
globally segmentally Intracapillary atrophy and
No. of sclerotic sclerotic Mesangial hematopoietic Features of interstitial Arterio- Arteriolar
Patient glomeruli glomeruli glomeruli Mesangial sclerosis hypercellularity cells chronic TMA fibrosis sclerosis hyalinosis

1 36 44 14 Moderate/diffuse Marked/diffuse Yes Yes Mild Moderate Mild

2 7 14 14 Mild/focal Moderate/focal No No Mild Marked Mild
3 25 56 16 Mild/diffuse Marked/diffuse No Yes Marked Mild Mild
4 31 32 23 Mild/diffuse Moderate/diffuse No Yes Mild Mild Mild
5 15 60 0 Mild/diffuse Moderate/focal No Yes Moderate Marked Mild
6 26 50 12 Moderate/diffuse Mild/focal No Yes Mild Mild Mild
7 11 55 18 Mild/diffuse Moderate/focal No No Marked None Mild
8 12 17 17 Mild/diffuse Mild/diffuse Yes Yes Mild Mild None
9 34 6 0 Moderate/diffuse Marked/diffuse Yes Yes Mild Moderate Mild
10 9 22 0 Moderate/diffuse Mild/focal No Yes Mild None Moderate
11 27 55 7 Moderate/diffuse Marked/diffuse Yes Yes Moderate Mild Mild
Abbreviation: TMA, thrombotic microangiopathy.

angiotensin II receptor blocker in one). Of the remaining

four patients, three were treated with steroids and one was
treated with mycophenolate mofetil. The latter patient (#8)
also underwent splenectomy, which showed extramedullary
hematopoiesis and a large infarct (Table 1). At follow-up,
seven patients had persistent renal dysfunction with protei-
nuria and renal insufficiency, whereas the remaining four
patients (including three of the four who received steroids)
progressed to end-stage renal disease (ESRD). Three patients
died, including two who had persistent renal dysfunction and
one who reached ESRD.

Pathological findings
Sampling for light microscopy included mean 21 glomeruli
(range 7–36 glomeruli). A mean of 37% of glomeruli were
globally sclerotic (Table 2). All cases showed some degree
mesangial sclerosis and hypercellularity (Figure 1). Mesangial Figure 1 | A glomerulus showing moderate global mesangial
sclerosis and mild mesangial hypercellularity. The glomerular
sclerosis was mild in six cases and moderate in five, whereas basement membrane appears mildly thickened and shows rare
mesangial cell hypercellularity was mild in three cases, double contours (periodic acid-Schiff,  400).
moderate in four, and marked in four. None of the cases
showed nodular mesangial sclerosis. Mild glomerulomegaly
was present in seven cases (64%). Eight cases (73%) exhibited
lesions of FSGS affecting 7–23% of the glomeruli sampled.
The segmental lesions featured increased extracellular matrix,
luminal hyalinosis, loss of overlying podocytes, and adhe-
sions to Bowman’s capsule (Figure 2). The segmental lesions
were predominantly perihilar in four cases. Segmental
glomerular basement membrane (GBM) double contours
were seen in seven cases (64%) on light microscopy, and were
particularly widespread in two cases (#1, 9; Figure 2).
Glomerular intracapillary infiltrating hematopoietic cells
were seen in four cases (36%), including megakaryocytes in
four (confirmed by positive staining for CD61; Figure 3) and
mature and immature granulocytes in three (confirmed by
positive staining for myeloperoxidase; Figure 4). None of the
cases showed intracapillary fibrin thrombi, crescents, or
fibrinoid necrosis. Figure 2 | This glomerulus shows a lesion of segmental
All cases had some degree of tubular atrophy and sclerosis with prominent luminal hyalinosis and adhesion to
interstitial fibrosis, which was mild in seven cases, moderate Bowman’s capsule. The rest of glomerular tuft exhibits mild
global mesangial sclerosis and widening of the subendothelial
in two, and marked in two. Mild chronic interstitial infla- zone associated with duplication of the glomerular basement
mmation composed of mainly lymphocytes and monocytes membrane (periodic acid-Schiff,  400).

Kidney International (2011) 80, 753–759 755

original article
a a
b b
Figure 3 | Intracapillary hematopoietic cells. (a) The glomerulus
at the center of the field exhibits an intracapillary marginated
megakaryocyte (arrow) and moderate global mesangial
hypercellularity. The glomerulus at the left lower shows moderate
mesangial sclerosis (periodic acid-Schiff,  400). (b) CD61
immunostain highlights two intracapillary marginating
megakaryocytes (arrows) and multiple intracapillary platelets
( 400).
was seen in areas of interstitial fibrosis in all cases, however,
none had interstitial neoplastic infiltrates. Arteriosclerosis
was seen in nine cases and ranged from mild in five cases, to
moderate in two, and to severe in two. Arteriolar hyalinosis
was seen in 10 cases, and was mild in 9 cases and moderate in
1. None of the cases showed arteriolar thrombosis or arterial
mucoid intimal edema. The renal biopsy from one patient
with PMF (#2) showed perirenal extramedullary hematopoi-
esis, whereas the renal biopsy from another patient with PMF
(#7) sampled a portion of perirenal sclerosing extramedullary
hematopoietic tumor. The latter is a rare lesion encountered
in patients with MPN (especially PMF) and is most
commonly seen in the retroperitoneum.9
None of the nine cases in which glomeruli were sampled
for IF revealed evidence of immune-complex glomerulone-
phritis. Glomeruli were negative for IgG, IgA, kappa, and
lambda in all cases. Seven cases showed nonspecific
756
SM Said et al.: Myeloproliferative neoplasm-related glomerulopathy
Figure 4 | Intracapillary hematopoietic cells. (a) Numerous
intracapillary marginating mature and immature granulocytes are
seen. The mesangial areas are expanded by mesangial
hypercellularity, sclerosis, and mesangiolysis, leading to lobular
accentuation of the tuft. There is also global duplication of the
glomerular basement membrane (periodic acid-Schiff,  400). (b)
Myeloperoxidase immunostain highlights multiple intracapillary
marginating immature granulocytes ( 400).
segmental and focal staining for C3, C1q, and/or IgM in
areas of glomerular sclerosis/hyalinosis.
EM, performed in all 11 cases, showed mesangial sclerosis
and hypercellularity (Figure 5) with GBM thickening. The
range of mean GBM thickness for the 11 cases was
463–1122 nm. Mild glomerular features of chronic TMA were
seen in nine cases (82%), including segmental GBM double
contours with or without mesangial interposition in eight cases,
mild segmental widening of the subendothelial zone by electron
lucent material (‘fluff’) in six cases, and mild mesangiolysis
in three cases. Intracapillary platelet thrombi were seen in one
case (#11; Figure 6). None of the 11 cases showed immune-
complex-type electron dense deposits. In one case (#6), rare
endothelial tubuloreticular inclusions were present. No tubu-
loreticular inclusions were seen in patient #10 who was treated
with interferon. The percentage of podocyte foot process
effacement ranged from 30 to 95% (average 63.2%).
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SM Said et al.: Myeloproliferative neoplasm-related glomerulopathy
Figure 5 | This electron micrograph shows mesangial sclerosis
and hypercellularity. The glomerular basement membranes
appear mildly thickened. There are no immune-type electron
dense deposits. Podocytes exhibit almost complete foot process
effacement ( 1400).
Figure 6 | This glomerulus from patient #11 who had
polycythemia vera exhibits an intracapillary platelet
thrombus (star) together with mesangial sclerosis and
hypercellularity. Podocytes exhibit almost complete foot process
effacement (electron microscopy,  1400).
DISCUSSION
MPN-related glomerulopathy appears to be a late complication
of MPN, as the mean time from diagnosis of MPN to renal
biopsy was 7.2 years in our cohort. Out of 11 of our patients, 8
(73%) had PMF, which is less common than PV, ET, and
CML,10,11 suggesting that PMF patients are most at risk to
develop MPN-related glomerulopathy. The most common
clinical presentation of MPN-related glomerulopathy is
nephrotic-range proteinuria (with or without full nephrotic
syndrome) and chronic renal insufficiency. Proteinuria was
often present for some time (mean 24 months) before biopsy.
There have been several cases of glomerulopathy in
patients with MPN described in the literature. Au et al.7
reported five patients with MPN and proteinuria. Kidney
Kidney International (2011) 80, 753–759
original article
biopsy revealed diffuse mesangial sclerosis and FSGS. In their
short report, there was no description of mesangial
hypercellularity, which was a unifying feature in our cases.
The case reported by Perazella et al.,8 however, was
histologically similar to our cases with both mesangial
hypercellularity and mesangial sclerosis together with glo-
merular intracapillary infiltrating hematopoietic cells. Saigu-
sa et al.12 reported a patient with ET who presented with
nephrotic syndrome. Kidney biopsy revealed FSGS with
mesangial hypercellularity and features of chronic TMA.12
There were also few additional case reports of FSGS in
patients with PV, PMF, and ET.13–17 Haraguchi et al.17
reported a patient with ET and FSGS, in whom elevated
serum levels of transforming growth factor-b (TGF-b) and
platelet-derived growth factor (PDGF) were documented.
The morphological differential diagnosis of MPN-related
glomerulopathy includes diabetic glomerulosclerosis, smok-
ing-related glomerulopathy (which may exhibit diffuse
mesangial sclerosis without nodule formation), primary
FSGS, TMA, and chronic membranoproliferative glomer-
ulonephritis. Mesangial hypercellularity is more prominent in
MPN-related glomerulopathy than diabetic glomerulosclero-
sis, smoking-related glomerulopathy, and primary FSGS,
whereas nodular mesangial sclerosis is typically not a feature
of MPN-related glomerulopathy. The absence of immune
deposits by IF and EM distinguishes MPN-related glomer-
ulopathy from membranoproliferative glomerulonephritis. In
patients with mesangial sclerosis and hypercellularity, the
finding of intracapillary hematopoietic cells (with megakar-
yocytes being the most easily identified) is very helpful in
differentiating MPN-related glomerulopathy from the above
entities. Although 81% of our cases had segmental duplica-
tion of GBM with subendothelial electron lucent ‘fluff ’,
mimicking a chronic TMA, they lacked glomerular intra-
capillary fibrin thrombi, arterial and arteriolar thrombotic
lesions, and clinical features of microangiopathic hemolytic
anemia (such as peripheral schistocytes). In addition, the
degree of mesangial hypercellularity and sclerosis was greater
than typically encountered in hemolytic uremic syndrome
and other forms of TMA.
The renal outcome in our cohort was guarded. Despite
treating the underlying MPN and renin–angiotensin system
blockade, four patients progressed to ESRD and the
remaining seven continued to have persistent renal dysfunc-
tion. Three of the four patients who ultimately reached
ESRD had received steroids. These limited data suggest that
steroids may not be effective in treating MPN-related
glomerulopathy. Larger studies with longer follow-up are
needed to determine the risk factors for development of
MPN-related glomerulopathy, the optimal therapeutic regi-
men, and whether more aggressive therapy of the underlying
neoplasm is beneficial in slowing the progression of
glomerulopathy. The relatively long-standing MPN before
the development of renal manifestations or diagnosis of the
renal disease may have contributed to the irreversible
glomerular disease and poor prognosis. Of note, all our
757
original article
patients with MPN-related glomerulopathy were older than
60 years of age and most of them had a history of
hypertension; therefore, the glomerulosclerosis, cortical
scarring, renal insufficiency, and guarded outcome in these
patients may be partially attributed to hypertensive or age-
related progressive vascular sclerosis.
Although the myeloproliferation in MPN results from a
clonal expansion of progenitor cells, the subsequent myelofi-
brosis that defines PMF is thought to be a reactive process
mediated by megakaryocyte-derived overproduction of
growth factors such as PDGF and TGF-b.18,19 In PMF, there
is bone marrow deposition of both interstitial and basement
membrane types of collagen, including collagen type I, III, IV,
V, and VI.20 PDGF and TGF-b likely have a crucial role in the
pathogenesis of MPN-related glomerulopathy. PDGF is the
most potent stimulus of mesangial cell proliferation21,22 and
it also induces extracellular matrix production by mesangial
cells.21,23 In five out of six nephrectomized rats, mesangial
cell proliferation and increased expression of PDGF precede
glomerulosclerosis.24 TGF-b induces mesangial sclerosis by
enhancing the synthesis of collagen and fibronectin by
mesangial cells.25,26 In addition to elevated serum levels, it
is possible that the above cytokines are produced locally in
the glomerulus by sludged and activated platelets/megakar-
yocytes, possibly augmented by paracrine effects on indigen-
ous mesangial cells. This is supported by the findings in our
study of thrombocytosis in 82% of patients and glomerular
intracapillary marginating platelets/megakaryocyte in 45% of
cases. TGF-b also has pro-apoptotic podocyte effects, which
may promote podocyte depletion and the FSGS lesions seen
in most cases.27,28 Intracapillary platelet aggregation and
activation may also lead to mild chronic endothelial cell
injury, which could explain the features of chronic TMA seen
in many of our cases. Microvascular red blood cell sludging at
the level of glomerular capillaries likely has a pathogenetic
role in PV-related glomerulopathy. Interestingly, the glomer-
ular pathology bears some similarities to sickle cell
glomerulopathy, which also exhibits a spectrum of FSGS,
glomerulomegaly and features of chronic TMA, and is
thought to be mediated by hemodynamic effects and
erythrocyte sludging in the glomerular capillary bed.29
Multiple forms of glomerular disease, both systemic and
renal-limited, can be linked pathogenetically to underlying
hematological neoplasms. Most of these are mediated by
production of a monoclonal paraprotein by a malignant
plasma cell or B lymphocyte clone. Primary amyloidosis,
monoclonal immunoglobulin deposition disease, and im-
munotactoid glomerulopathy are the most common glomer-
ular lesions in patients with plasma cell dysplasia,30–32
whereas minimal change disease and cryoglobulinemic
glomerulonephritis type I are the most frequent in patients
with lymphoma.33,34 On the basis of our study and the
previously reported cases of MPN-related glomerulopathy,
patients with MPN develop a distinct glomerular lesion that
differs morphologically and pathogenetically from those seen
in other types of hematological neoplasms.
758
SM Said et al.: Myeloproliferative neoplasm-related glomerulopathy
There are limitations to our study that relate to its
retrospective nature and small size. Unfortunately, we were
unable to assess the incidence of MPN-related glomerulop-
athy in patients with MPN or determine the serum levels of
growth factors because most patients were followed at
outside institutions. Despite these limitations, this small
series will hopefully raise the awareness of hematologists,
nephrologists, and pathologists to this potential complication
of MPN, leading to larger studies aimed at determining the
incidence, pathogenesis, and optimal management.
In summary, this report of MPN-related glomerulopathy
enlarges the spectrum of glomerular diseases associated with
hematological neoplasms. MPN-related glomerulopathy is an
under-recognized late renal complication of MPN with poor
prognosis. It is characterized clinically by heavy proteinuria
and renal insufficiency and histologically by variable degrees
of mesangial sclerosis and hypercellularity, segmental sclero-
sis, features of chronic TMA, and intracapillary hematopoi-
etic cell infiltration. Greater awareness is needed to determine
the overall incidence and potential reversibility.
MATERIALS AND METHODS
We reviewed the renal pathology archives at Mayo Clinic, Rochester,
from 2000 to 2010, and identified 11 patients with history of MPN
who had mesangial sclerosis and hypercellularity without evidence
of immune complex glomerulonephritis on IF or EM. The diagnoses
of MPN were established according to the criteria proposed by
WHO (for PMF) and PVSG (for PV and ET).35–37 The diagnosis of
CML was based on the presence of characteristic findings in the
blood and bone marrow and positive Philadelphia chromosome.
Patients with history of diabetes or glucose intolerance were
excluded form this study. During the study period, in addition to
the 11 patients included in this study, there were 6 non-diabetic
patients with renal biopsies who carried a history of MPN and for
whom we were able to confirm that they fulfilled the diagnostic
criteria for MPN. Of these, three had chronic TMA without
significant mesangial sclerosis or hypercellularity; one had acute
post-infectious glomerulonephritis; one had segmental membra-
nous glomerulopathy with FSGS; and one had thin basement
membrane disease. These six patients did not fulfill the study entry
criteria and therefore were excluded.
Standard processing of renal biopsies included light microscopy,
IF, and EM. For light microscopy, all cases were stained with
hematoxylin and eosin, periodic acid-Schiff, Masson’s trichrome,
and Jones methenamine silver. For IF, 3-mm cryostat sections were
stained with polyclonal Fluorescein isothiocyanate-conjugated
antibodies to IgG, IgM, IgA, C3, C1q, kappa, lambda, fibrinogen,
and albumin (Dako, Carpinteria, CA). Immunoperoxidase studies
were performed on paraffin sections of the kidney biopsy using
antibodies directed against CD61 (Vision BioSystems, Norwell,
MA), which is a marker for megakaryocytes and platelets and
against myeloperoxidase (Dako), which is a marker for mature and
immature granulocytes.
Clinical data, including demographic information, presenting
renal clinical and laboratory findings, and hematological clinical and
laboratory findings including findings of bone marrow biopsy/smear
and peripheral smear, treatment and follow-up, were obtained from
referral forms submitted at the time of biopsy, patients’ medical
records, and telephone interviews with the treating nephrologists
Kidney International (2011) 80, 753–759
SM Said et al.: Myeloproliferative neoplasm-related glomerulopathy
and hematologists. The following clinical definitions were used:
nephrotic-range proteinuria X3.0 g/day; hypoalbuminemia, serum
albumin o3.5 g/dl; renal insufficiency, serum creatinine 41.2 mg/dl;
nephrotic syndrome, nephrotic-range proteinuria, hypoalbumine-
mia, and peripheral edema. Mesangial hypercellularity was defined
as 43 mesangial cells per mesangial area (focal, affecting o50% of
glomeruli; diffuse, affecting X50% of glomeruli) and was graded as
mild (4–5 mesangial cells/mesangial area), moderate (6–7 mesangial
cells/mesangial area), and severe (X8 mesangial cells/mesangial
area).38 The degree of mesangial sclerosis was scored on a
semiquantitative scale of mild, moderate, and marked based on
the extent of mesangial expansion (focal, affecting o50% of
glomeruli; diffuse, affecting X50% of glomeruli). Tubular atrophy
and interstitial fibrosis were graded on a semiquantitative scale
based on an estimate of the percentage of renal cortex affected and
recorded as: 0 (none), 1–25% (mild), 26–50% (moderate), or 450%
(severe). The study was approved by the Institutional Review Board
of Mayo Clinic Foundation.
DISCLOSURE
All the authors declared no competing interests.
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