Ian W. Gibson, Associate Professor, Pathology, University of Manitoba
An Unusual Cause of Acute Renal Failure in Sickle Cell Disease
A 20-year-old female was followed in a Canadian nephrology clinic. She was originally from the
African nation of Guinea and had immigrated to Canada ten years previously. Her past medical history
included sickle cell disease, multiple blood transfusions from the resultant anemia, and numerous
painful vaso-occlusive crises. At the age of 19 years, she presented to the hospital emergency
department with three weeks of swelling in both legs and puffiness around her eyes. The anasarca was
treated with intravenous diuretics. At the time, serum creatinine was 140 μmol/L and a 24-hour urine
collection revealed 14.4 g/day of protein.
A first renal biopsy was performed to explain the cause of nephrotic syndrome. It showed diffuse
mesangial proliferative and crescentic glomerulonephritis due to IgA nephropathy. Subsequent treatment
included six months of oral prednisone and IV cyclophosphamide followed by oral azathioprine. During
the year of treatment with prednisone, the patient developed avascular necrosis of both hips, but she did
not require surgical intervention. After six months of azathioprine (therefore more than a year after the
first renal biopsy), the serum creatinine began to increase from a baseline of 138 μmol/L to 485 μmol/L
three months later, and the patient was subsequently admitted urgently to hospital with pulmonary
edema. She had not noticed any hematuria or dysuria, but did have diffuse myalgias and pruritus.
Bloodwork done on day of hospital admission revealed a creatinine of 828 umol/L. Urinalysis at this
time showed pH<6, negative for glucose, ketones and bilirubin, 51-100 red blood cells per high power
field and 6-10 white blood cells per high power field. The spot urine protein:creatinine ratio was 1093.2
mg/mmol. Fasting cholesterol was obtained and showed triglycerides 1.3 mmol/L and LDL 2.3 mmol/L.
A complete blood count with differential and blood film showed white blood cell count 4.7 x109/L,
haemoglobin 104 g/L, and platelets 116 x109/L. There were schistocytes (3-5 per high power field),
echinocytes, and Howell Jolly bodies seen. A renal ultrasound showed symmetric kidneys (right 11 cm,
left 10 cm) with no calculi and no obstruction. Her blood pressure at time of admission was significantly
elevated, and she subsequently developed hypertension up to 190/120. She was started on urgent
hemodialysis and a second renal biopsy was performed a day later. The submitted images are from this
second renal biopsy.
Kidney Biopsy Findings
There were 2 cores, one comprising renal cortex and medulla and a smaller core of medulla only. There
were up to 18 glomeruli, up to 9 of which were globally sclerosed. A further 5 glomeruli showed
varying degrees of segmental sclerosis with tuft-to-capsule adhesions, some forming fibrous crescents.
There were 3 glomeruli showing segmental thrombotic and fibrinoid injury, 3 glomeruli showed active
cellular crescentic injury, some glomeruli showed segmental mesangial hypercellularity and there were
scattered granulated glomerular epithelial cells. Glomerular capillary walls were focally thickened, with
scattered double contour formation. The tubular epithelium showed focal cytoplasmic vacuolation,
sloughing of degenerate cells and focally prominent hyaline droplet change. There were scattered PAS-
positive Tamm Horsfall protein casts within tubules. Medullary vasa recta showed prominent
inflammatory cell accumulation, including a significant number of marginating neutrophil polymorphs.
There was patchy mild chronic interstitial inflammation and patchy moderate-to-severe tubular atrophy
and interstitial fibrosis. Arteries showed mild-to-moderate fibrous intimal thickening and no evidence of
vasculitis. Up to 3 arterioles show fibrinoid necrosis, some with associated thrombosis, particularly at
glomerular vascular poles. The Sirius red amyloid stain was negative.
The frozen core for direct immunofluoresence consisted of cortex with up to 9 glomeruli, some showing
segmental sclerosis. There was segmental glomerular staining for IgM (1+) and C3 (1+), consistent with
areas of segmental sclerosis. Staining for IgA showed non-specific staining of glomerular epithelial cell
granules, but there was no mesangial or capillary wall staining for IgA. A repeat IgA stain confirmed
these findings. Glomeruli were also negative for IgG, C1q, fibrinogen and kappa and lambda light
chains. Arterioles show staining for IgM (2+), C3 (2+) C1q (1+) and fibrinogen (2+).
Four glomeruli were available for ultrastructural examination, 3 of which were extensively sclerosed.
The non-sclerotic glomerulus showed segmental thrombosis with platelet and fibrin thombi occluding
the arteriole and glomerular capillaries. Glomerular capillary walls were markedly thickened with
subendothelial widening, focal subendothelial fibrin deposition, prominent mesangial cell interposition
and reduplication of glomerular basement membrane. There was widespread epithelial cell foot process
fusion with surface microvillous transformation. No immune complex-type deposits were identified.
The features were of acute microvascular injury with arteriolar fibrinoid necrosis, arteriolar and
glomerular thrombotic microangiopathy, and active glomerular crescentic injury, superimposed upon a
chronic membranoproliferative-like pattern of glomerular injury. There was severe chronic irreversible
glomerular damage with global and focal segmental glomerulosclerosis and patchy moderate-to-severe
chronic tubulointerstitial damage. There was no evidence of immune complex-mediated
Final diagnosis – Acute-on-chronic renal thrombotic microangiopathy, with features consistent
with chronic sickle cell nephropathy.
Since the concern was a rapidly progressive glomerulonephritis, this patient received five treatments of
plasmapheresis. Cyclophosphamide was restarted because it was speculated at first that she had had a
relapse of IgA nephropathy. The patient developed tonic-clonic seizures during the month after her
decompensated renal failure. After the first seizure, a computed tomography scan and a magnetic
resonance image (MRI) of the brain were both normal. Several weeks later, she seized again, and the
findings of a further MRI scan were consistent with reversible posterior leukoencephalopathy syndrome
(RPLS). Patients with RPLS present with headache, nausea, vomiting, confusion, visual disturbance, and
seizures (1). The typical MRI findings include symmetrical white matter edema in the posterior cerebral
hemispheres, particularly in the parieto-occipital regions. This syndrome most often occurs in the setting
of a hypertensive crisis, preeclampsia/eclampsia, connective tissue diseases, thrombotic
thrombocytopenic purpura or with cytotoxic immunosuppressive therapy. In some settings, uremia,
sepsis, hypomagnesemia and other metabolic disturbances have been implicated, and fluid overload may
contribute. Most patients recover within two weeks. The patient had developed significant hypertension,
with blood pressure readings up to 192/125, she was being treated with cyclophosphamide and she may
also have been uremic. Cyclophosphamide therapy was discontinued after the second seizure. Platelet
counts during this post-biopsy period were between 140 and 200 x109/L.
Fluid control was an ongoing issue with this patient as she had been told from a very young age to drink
a lot of water to decrease the risk of vaso-occlusive crises from sickle cell disease. Now, as a dialysis
patient, she was advised to limit her water intake. Subsequently, she had several emergency room visits
for fluid overload and hyperkalemia, all requiring urgent hemodialysis. There was no renal functional
recovery and the patient was transitioned from hemodialysis to peritoneal dialysis.
Sickle cell disease was first described by Herrick in 1910 (2). In 1948, it was noted that symptoms of
anemia in infants appear only after the concentrations of hemoglobin F fall. The condition, which
protects heterozygous carriers from succumbing to Plasmodium falciparum malaria, is an autosomal
recessive hereditary hemoglobinopathy. There is a single amino acid substitution of valine for glutamic
acid due to a point mutation in the 6th codon of the β-globin gene on chromosome 11p15.5, causing
sickling of deoxygenated red blood cells and development of microvascular occlusions (3).
Five to 18% of sickle cell disease patients develop renal failure. By multivariate regression analysis,
renal failure has been identified as the major risk factor for early mortality in adult patients with sickle
cell disease (4). Renal pathophysiological and clinical manifestations associated with sickle cell disease
are numerous, and reflect both glomerular and tubular disorders (5,6). Features include impaired urinary
concentrating ability (hyposthenuria), incomplete renal tubular acidosis, impaired potassium secretion,
hematuria and proteinuria. In patients who are more than ten years old, the maximum urinary
concentration with water deprivation is often reduced to 400 to 450 mOsmol/kg H20. The hyposthenuria
can lead to higher than usual obligatory urine output, with increased risk of dehydration. Regarding
renal tubular acidosis, the distal tubule requires greater acidic stimulus to reach a maximum urine-to-
blood hydrogen ion gradient. There is no proximal loss of bicarbonate, and it does not cause systemic
metabolic acidosis. Hematuria is a prevalent feature of sickle cell disease, related to renal medullary
injury. The hematuria is often unilateral, with the left kidney being four times more frequently involved,
because of increased venous pressure due to greater length of the left renal vein. Proteinuria is seen in up
to 40% of patients with sickle cell disease, and nephrotic syndrome is common in sickle cell
nephropathy, thought to be mediated by glomerular capillary hypertension and hyperfiltration.
The usual clinical pattern of sickle cell nephropathy is of chronic progressive renal failure leading to
end-stage renal disease (5,6). Acute renal failure associated with sickle cell disease has also been
described, usually in association with other precipitating factors such as sepsis or rhabdomyolysis (7), or
in the context of multiorgan failure in sickle cell crisis with massive generalized sickling (8).
Renal pathologic findings reported in patients with sickle cell disease include papillary necrosis (9),
glomerular hypertrophy and secondary hyperfiltration-mediated perihilar focal segmental
glomerulosclerosis (10), immune complex-mediated type 1 membranoproliferative glomerulonephritis
(MPGN) with glomerular immunoglobulin and complement deposition (11,12) and an MPGN-like
pattern of glomerular injury with glomerular basement membrane reduplications but without immune
deposits (13,14). Additional non-specific features described include proximal tubular cell iron
pigmentation, tubular atrophy, interstitial fibrosis and chronic inflammation, particularly in the renal
medulla. The postulated mechanism of renal injury is that the hypoxic, acidotic, hyperosmolar
environment of the inner medulla promotes sickling of red cells in the medullary vasa recta, with
resultant increased blood viscosity, impairment in renal medullary blood flow, microthrombi formation,
ischemic microinfarcts and progressive renal medullary injury with papillary necrosis (6). An
association with renal medullary carcinoma is also recognised (15).
Thrombotic microangiopathy (TMA) encompasses non-inflammatory small vessel vasculopathies,
usually associated with severe endothelial or medial myocyte injury and microvascular platelet
thrombosis. Commonly recognised causes of renal TMA (16) include haemolytic uremic syndrome
(typically associated with verotoxin-producing E. coli 0157 enterocolitis), thrombotic thrombocytopenic
purpura, antiphospholipid antibody syndrome (either primary or secondary to systemic lupus
erythematosus or other connective tissue disease), scleroderma renal crisis, malignant phase
hypertension, disseminated intravascular coagulation, pregnancy-associated TMA, radiation and other
therapy-associated TMA, and transplant-associated TMA (including calcineurin inhibitor toxicity and
antibody mediated rejection).
In this case, the patient did not have enterocolitis symptoms and she did not have thrombocytopenia.
Hypertension was a significant feature at the time of the second renal biopsy, and became increasingly
severe subsequent to the biopsy. Antiphospholipid antibody was not measured. She had been taking the
oral contraceptive pill, which is a recognised cause of TMA. The diagnosis of IgA nephropathy from
the 1st renal biopsy was not corroborated in the 2nd renal biopsy; renal TMA is not a commonly
recognised association with IgA nephropathy.
Acute TMA is not a commonly recognised complication of sickle cell disease, with the glomerular
capillary and arteriolar congestion by sickled erythrocytes not typically associated with fibrin thrombi.
The renal pathological features in this case suggest an acute TMA, likely exacerbated by severe
hypertension, superimposed upon chronic MPGN-like glomerular changes. The MPGN-like glomerular
lesion observed in chronic sickle cell nephropathy has been speculated to be produced by continuous
mesangial cell phagocytosis of fragmented red cell masses in glomerular capillaries, with associated
remodelling of glomerular basement membrane and mesangial cell interposition (13,14). Similar
ultrastructural changes are observed in rats with intravascular fibrin formation (17) and in human renal
biopsies with healing haemolytic uremic syndrome (18). So the MPGN-like chronic glomerular lesion of
sickle cell disease could be regarded as a chronic TMA-related lesion.
A possible link between sickle cell disease and acute-on-chronic renal TMA is the presence of
circulating microparticles (19). Microparticles are intact vesicles, 0.2 to 2.0 microns diameter, derived
from budding and shedding cell membranes of vascular endothelium or circulating blood cells. They
arise through cell membrane activation processes and from apoptosis. Thrombotic thrombocytopenic
purpura is characterised by failure to cleave the highly pro-thrombotic multimers of von Willebrand
Factor in the circulation, and elevated levels of platelet and endothelial-derived microparticles have been
described in that condition. Detected in the circulation of patients with sickle cell disease, circulating
microparticles appear during chronic phases and in crises (20). In the chronic phase, there is chronic
hemolysis and chronic activation of coagulant pathways, resulting in low-grade thrombin generation,
depletion of anticoagulants and activation of leucocytes and platelets. These pro-coagulant and pro-
inflammatory processes are associated with endothelial cell damage and microparticles derived from
endothelial cells, platelets and monocytes. During sickle crises, the endothelial damage and coagulation
activity increases dramatically, accompanied by a rise in circulating microparticles of platelet,
endothelial, red blood cell, and monocyte origin (20,21). Circulating microparticles are therefore a
possible cause of TMA in sickle cell disease patients.
In conclusion, this is a case of a young female with sickle cell disease, diagnosed by biopsy with
crescentic IgA nephropathy, which was treated with resolution of creatinine, then a year later when renal
function declined, repeat renal biopsy showed acute-on-chronic TMA and features consistent with
chronic sickle cell nephropathy. Circulating microparticles could be the pathophysiological link between
the sickle cell disease and development of renal TMA. This case also emphasizes the importance of a
further renal biopsy for acutely declining renal function, even when a definite renal diagnosis has been
made from a previous renal biopsy.
Clinical information and parts of the discussion contributed by Dr Maryanne Rockx, Nephrology
Fellow, University of Manitoba.
1. Zhang YX, Liu JR, Ding MP, Huang J, Zhang M, Jansen O, Deuschl G, Eschenfelder CC.
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2. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.
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3. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004; 364:1343-60.
4. Platt RS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in
sickle cell disease. N Engl J Med 1994; 330:1639-1644.
5. Saborio P, Scheinman JI. Sickle cell nephropathy. J Am Soc Nephrol 1999; 10:187-92.
6. Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in sickle cell disease. Kidney
Int 2000; 57:1-8.
7. Devereux S, Knowles SM. Rhabdomyolysis and acute renal failure in sickle cell disease. Br Med J
8. Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic
complication of sickle cell pain episodes. Am J Med 1994; 96:155-162.
9. Vaamonde CA. Renal papillary necrosis in sickle cell hemoglobinopathies. Semin Nephrol 1984;
10. Falk RJ, Scheinman J, Phillips G, Orringer E, Johnson A, Jennette JC. Prevalence and pathological
features of sickle cell nephropathy and response to inhibition of angiotensin converting enzyme. N
Engl J Med 1992; 326:910-915.
11. Pardo V, Strauss J, Kramer H, Ozawa T, McIntosh RM. Nephropathy associated with sickle cell
anemia: an autologous immune complex nephritis. II. Clinicopathological study of seven patients.
Am J Med 1975; 59:650-659.
12. Iskandar SS, Morgann RG, Browning MC, Lorentz WB. Membranoproliferative
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13. Elfenbein IB, Patchefsky A, Schwartz W, Weinstein AG. Pathology of the glomerulus in sickle
cell anemia with and without nephrotic syndrome. Am J Pathol 1974; 77:357-374.
14. Bakir AA, Hathiwala SC, Ainis H, Hryhorczuk DO, Rhee HL, Levy PS, Dunea G. Prognosis of the
nephrotic syndrome in sickle glomerulopathy. A retrospective study. Am J Nephrol 1987: 7:110-
15. Davis CJ, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma: The seventh sickle cell
nephropathy. Am J Surg Pathol 1995; 19:1-11.
16. Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytric uremic syndrome,
and thrombotic thrombocytopenic purpura. Kidney Int 2001; 60:831-846.
17. Vassalli P, Simon G, Rouiller C. Electron microscopic study of glomerular lesions resulting from
intravascular fibrin formation. Am J Pathol 1963; 43:579-616.
18. Vitsky BY, Suzuki Y, Strauss L, Churg S. The hemolytic uremic syndrome. Am J Pathol 1969;
19. Piccin A, Murphy WG, Smith OP. Circulating microparticles: pathophysiology and clinical
implications. Blood Rev. 2007; 21:157-71.
20. Shet AS, Aras O, Gupta K, Hass MJ, Rausch DJ, Saba N, Koopmeiners L, Key NS, Hebbel RP.
Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and
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21. Manodori AB, Matsui NM, Chen JY, Embury SH. Enhanced adherence of sickle erythrocytes to
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Maria M. Picken MD, PhD
Loyola University Medical Center
HPI: in August 2007, a 25 year old female with a history of acute lymphoblastic leukemia (ALL) was
admitted with hypotension and lightheadedness. Blood pressure had been low since June and was
treated with Florinef. Dizziness became worse with standing and ambulation. She had had dry mouth
for a few weeks and passed 4-5 semi-formed stools daily.
FH: grandmother – throat carcinoma, grandfather – myocardial infarction, uncle – Hodgkin’s
lymphoma; no family history of kidney disease.
SH: stopped smoking 2 years ago, rare alcohol, no illicits
PMH: two years prior (June 2005) she was admitted to LUMC with 3-4 weeks of fatigue, petechiae,
night sweats, chills, 10 lbs weight loss, neck pain. Her WBC count was 170,000, her peripheral blood
showed marked leukocytosis with numerous circulating blasts, microcytic anemia and
thrombocytopenia. Her bone marrow was hypercellular (95% cellularity) consistent with involvement
by precursor B-cell Acute Lymphoblastic Leukemia.
She was treated with leukophoresis and chemotherapy. In July 2005, a repeat biopsy showed markedly
hypocellular (<5% cellularity) bone marrow with scattered lymphocytes and megakariocytes. There was
no morphologic evidence of leukemia. In September 2005, she underwent allogeneic matched sibling
stem cell transplant with engraftment on day +11. Tacrolimus was administered for GVHD prophylaxis,
and stopped on Day +122.
In February 2006, she had oral lesions consistent with chronic GVHD; treated with Dexamethasone and
Nystatin; subsequently, Tacrolimus 1mg daily.
One year post allotransplant, in September 2006, her bone marrow showed no morphologic evidence of
involvement by acute leukemia. After the biopsy, however, she complained of lower abdominal pain.
CT was ordered to r/o hematoma. However, radiologic studies showed left adnexal mass measuring 4.1
x 2.9 x 3.6 cm. In October 2006, she underwent laparoscopic left salpingo-ophorectomy, which showed
ovary involved by precursor B-cell lymphoblastic lymphoma. Her peritoneal fluid was also positive for
lymphoblasts. In November 2006, she received salvage chemotherapy with Idarubicin, Cytarabine,
Etoposide and Donor Lymphocyte Infusion. In December 2006, she underwent CT scans to rule out
relapse. There was no pelvic lymphadenopathy, mass or fluid collection. There was a focal eccentric
colonic wall thickening in splenic flexure. Hemicolectomy (January 2007) demonstrated a >10 cm
mass at splenic flexure, which showed involvement by precursor B cell acute lymphoblastic
leukemia/lymphoma. Her bone marrow biopsy was again negative for ALL. In February-March 2007,
the patient received maintenance chemotherapy in preparation for BMT. She received her second bone
marrow transplant (MUD) on 4/11/07 with induction with Cytoxan/Busulfan. Engraftment by 4/19/07.
Discharged on Prograf for GVHD prophylaxis.
ROS: Gen: NAD, no weight loss, no fevers. HEENT: no oral lesions. No lymphadenopathy. CV: no
chest pain, Respiratory – no shortness of breath, GI: (+) diarrhea, no BRBPR, GU: no dysuria, flank
pain. Muscular: no muscle or joint pain, Neuro: no focal complaints.
PE: T 36.80C, RR 12, Supine: 77/40, 100, Sitting 44/33, 124
Gen: NAD, HEENT: PERRL, MMM, Neck: no lymphadenopathy, lungs clear. CV: normal S1, S2; no
m/r/g. Abdomen: soft, non tender, not distended, bowel sound present, no tenderness, no HSM.
Extremities: (+) pedal edema; 2+ dp pulses b/l. Neuro: no focal deficits.
Labs: 134/4.0; 101/27; 12/0.64, 100, 8.4; 10.6, 12.6, 407
Albumin 1.2, Protein 4.9, Alk Phos 123, Bilirubin 0.4, AST 33, ALT 18, LDH 154
INR 1.0, PTT 32.5
UA: yellow, pH 7.0, SG 1.025, protein (4+), Neg nitrite, Neg LE, RBC (1), WBC (3), hyaline casts (53),
granular casts (4)
SPEP: protein- 3.2(L), albumin 1.2, alpha 1 – 0.1, alpha 2 - 1.1 (H), Beta – 0.5 (L), Gamma – 0.3 (L).
Free kappa – 7.9, free lambda – 14.7; free k/l ratio – 0.54
24 hr urine collections: Na – 132 mmol, K – 38.9mmol, Cl – 138mmol, Uric Acid -383mg, Creatinine –
0.8g, Calcium – to low to calculate, Mg – 40.6mg, Protein-9.36g
Renal US: R kidney – 11.6 cm; L kidney 12.0cm; normal echogenicity, no focal lesions, hydronephrosis
A kidney biopsy was performed.
Paraffin sections showed renal cortex and medulla. There were seven glomeruli per level on average, all
of which were unremarkable by light microscopy. There was interstitial, peri-tubular mononuclear
infiltrate with frequent tubulitis and degenerative changes in the tubular epithelium. Immunoperoxidase
stain for polyoma virus was negative. Immunoperoxidase stains for CD34, CD10, TdT, CD3, CD4 and
CD8 were examined and showed no evidence of lymphoma.
Immunofluorescence stains (with IgG, IgA, IgM, kappa and lambda light chain, C3, C1q, fibrinogen and
albumin) were negative or showed a non-diagnostic pattern.
By Electron microscopy no electron dense or fibrillar deposits were seen. There was a diffuse
effacement of the epithelial cell foot processes and villous transformation.
Molecular cytogenetic studies revealed 79.4% female cells and 20.6% male cells of donor origin in the
biopsy section, indicative of chimerism for host and donor cells.
- GRAFT VERSUS HOST DISEASE IN THE KIDNEY WITH MINIMAL CHANGE DISEASE AND
- NEGATIVE FOR LYMPHOMA
Post biopsy, following adjustment of immunosuppression, clinical symptoms of chronic GVHD
subsided with remission of nephrotic syndrome.
Nephrotic syndrome is a relatively rare complication of chronic GVHD. Only single case reports or
small series exist in the literature, totaling less than 50 patients that have been thus far reported. Two
thirds of patients were diagnosed with membranous nephropathy and one third with minimal change
disease; rare cases of focal and segmental glomerulosclerosis and other glomerular pathologies were
also reported (Hiesse et al 1988, Lin et al 2001, Sato et al 2004, Reddy et al 2006, Brukamp et al 2006,
Terrier at al 2007, Silva et al 2007, Kimura et al 2003).
A close temporal relationship between the development of nephrotic syndrome shortly after cessation of
immunosuppression and the diagnosis of chronic GVHD has been used as an argument to support their
etiologic relationship. However, rare cases of nephrotic syndrome in patients without evidence of
chronic GVHD have also been recently reported (Srinivasan et al, 2005, Kalayoglu-Besisik et al 2007,
Sugimoto et al 2007).
Other kidney pathologies in patients post hematopoietic bone marrow transplant have also been
reported, in particular those not associated with chronic GVHD, but little attention has been given to
tubulo-interstitial “nephritis” (Brukamp et al 2006, Chang et al 2007).
In previously reported patients with nephrotic syndrome and chronic GVHD, several biopsies showed
interstitial infiltrates of variable intensity, composed of lymphocytes, monocytes and macrophages
(Brukamp et al 2006, Terrier et al 2007). While in some patients this may be associated with relapse of
the primary hematologic malignancy, GVHD should be considered in the differential diagnosis. Similar
to this patient, three earlier studies confirmed the donor origin of mononuclear interstitial infiltrates
(Kimura et al 2003, Romagnani et al 2005, Terrier et al 2007). It therefore seems likely that interstitial
infiltrates of donor origin may also be an expression of GVHD in the kidney. Postmortem examination
of the kidney in allogeneic hematopoietic stem cell transplantation recipients showed that these patients
were more likely to have renal tubulitis and peritubular capillaritis compared to controls (patients with
hematologic malignancies receiving chemotherapy alone). Also, allo-SCT recipients with severe
GVHD tended to have tubulitis and capillaritis (Kusumi et al 2008). Whether these infiltrates are
always associated with glomerular pathology, or can occur alone, remains unanswered. While
glomerular lesions leading to nephrotic syndrome are clinically apparent, and usually prompt a kidney
biopsy, tubular involvement may be silent or associated with renal failure. Although no doubt
multifactorial, renal failure is certainly more common than nephrotic syndrome in patients post bone
marrow transplant and is also seen outside the setting of chronic GVHD. Thus, tubulitis, as an
expression of GVHD, may be under-diagnosed in bone marrow recipients.
Whether GVHD affects organs other than the classic triad of skin, gut and liver is an open question.
Recently, additional organ manifestations of GVHD have been reported, including lungs, central
nervous system and also synovitis (Deeg and Antin 2006, Nozzoli et al 2008). Kidney involvement in
GVHD may need to be considered as well.
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deposition following allogeneic bone marrow transplantation for natural killer cell
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Barrett J, Geller N, Childs R. Nephrotic syndrome: an under-recognised immune-mediated
complication of nonmyeloablative allogeneic haematolopoetic cell transplantation. Br J Haematol
10. Kalayoglu-Besisik S, Yurci A, Yazici H, Yonal I, Sargin D. Long-term outcome of nephrotic
syndrome in an allogeneic hematopoietic stemm cell recipient without typical features of graft
versus host disease. Transplantation 2007;83:1407-8.
11. Sugimoto T, Tanaka Y, Sakaguchi M, Osawa N, Tanaka Y, Uzu T, Kashiwagi A. A case of post-
allogeneic haematopoietic stem cell transplantation membranous nephropathy. Nephrol Dial
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Alpers CE. Spectrum of renal pathology in hematopoietic cell transplantation: a series of 20
patients and review of the literature. Clin J Am Soc Nephrol 2007;2:1014-23.
13. Romagnani R, Lazzeri E, Mazzinghi B, Lasagni L, Guidi S, Bosi A, Ciram C, Salvadori M.
Nephrotic syndrome and renal failure after allogeneic stem cell transplantation: novel molecular
diagnostic tools for a challenging differential diagnosis. Am J Kid Dis 2005;46:550-6
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Shibata T, Matsumura T, Yuji K, Masuoka K, Wake A, Miyakoshi S, Taniguchi S. Postmortem
examination of the kidney in allogeneic hematopoietic stem cell transplantation recipients: possible
involvement of graft-versus-host disease. In J Hematol 2008;87:225-30
15. Deeg HJ, Antin JH. The clinical spectrum of acute graft-versus-host disease. Sem Hematol
16. Nozzoli C, Guidi S, Paglierani M, Wnekowicz E, Saccardi R, Bosi A, Santucci M, Massi D.
Immunohistochemical and FISH analyses identify synovitis associated chronic GVHD after
allogeneic hematopoietic SCT. Bone Marrow Transplant 2008;42:289-91.
Vanderbilt University Medical Center
The patient is a 59-year-old African American male who presented with malaise, weakness and weight
loss. He has had no fevers or chills.
His past medical history is significant for asthma, benign prostatic hypertrophy, hypertension, cataract,
peptic ulcer, depression and insomnia.
On physical examination he showed no acute distress. His blood pressure was 148/100 mmHg, pulse 73
times/min, and temperature 97.7 F. He had bilateral lymphadenopathy at the base of the neck and in the
groin region. The lymph nodes were about 1.5 cm in diameter, fixed, hard and non-tender. Lungs were
clear to auscultation bilaterally. Abdomen was soft and no hepatosplenomegaly was identified. Lower
extremities showed no edema. There was no skin rash.
Laboratory workup revealed serum creatinine 2.3 mg/dl, BUN 64 mg/dl, glucose 79 mg/dl, sodium 134
mg/dl, potassium 4.4 mg/dl, chloride 109 mg/dl, bicarbonate 19 mg/dl, albumin 2.9 g/L, protein 8.4 g/L,
calcium 8.8 mg/dl, white count 6.1/mm3, platelets 339,000, hemoglobin 13.8 g/h and hematocrit 41.7.
He had eosinophilia in the range of 20%. His C-ANCA was mildly positive and P-ANCA was negative.
Hepatitis C and HIV serologies were negative. Serum protein electrophoresis was negative. He had
proteinuria in the range of 500 mg/24h. Ultrasound examination showed enlarged kidneys about 13 cm
in diameter bilaterally but no evidence of hydronephrosis or other signs of obstruction.
Inguinal and cervical lymph node biopsies showed extensive atypical histiocytic and plasma cell
infiltrates predominantly involving paracortical lymph node regions.
The patient’s renal function worsened over the following three months with serum creatinine levels
rising to 5.9 mg/dl. A renal biopsy was performed at that time.
Renal Biopsy Findings
The biopsy consisted of one tissue core of renal cortex containing four glomeruli, none of which was
globally sclerosed. There was no endocapillary proliferation, fibrinoid necrosis or crescent formation.
The capillary basement membranes appear to be of normal thickness. There are no adhesions to
Bowman capsule and there is no segmental sclerosis. The glomeruli show segmental basement
membrane corrugation and mild increase in mesangial matrix.
The tubular interstitial compartment shows diffuse interstitial infiltrate of large atypical histiocytic cells
with indistinct cell borders admixed with plasma cells, lymphocytes and occasional clusters of
eosinophils (>30/HPF). The atypical spindle-shaped histiocytic cells show elongated, villous
cytoplasmic processes infiltrating around mildly atrophic tubules in a whorled and fascicular growth
pattern. Immunohistochemistry stains for S100, vimentin and CD68 are strongly positive in these cells.
There is also focal positivity for CD 45. CD1a, CD 35, CD3, CD 20 and cytokeratin AE 1/3 stains are
negative in the atypical histiocytic cells.
Several interlobular arteries and arterioles show focal lymphocytic infiltrate in the adventitia and the
outer third of the media. However, no diagnostic vasculitic infiltrate is seen.
Immunofluorescence studies show trace speckled mesangial staining for IgG, C1q and polyvalent
antisera. There is 1+ arteriolar staining for C3.
Electron microscopy studies show extensive interstitial infiltrate of histiocytic cells with irregularly
shaped nuclear membranes and interdigitating long villous cytoplasmic processes. There are no
cytoplasmic dense core granules, no Birbeck granules and no junctional complexes. There is extensive
foot process effacement but no immune complex deposition. There are no reticular aggregates or fibrin
Summary: Based on the cellular morphology of the abnormal infiltrate, the absence of CD1a IHC stain
as well as absence of Birbeck granules by EM, a Langerhans cell tumor could be excluded as possible
diagnosis. The immunohistochemistry staining pattern and ultrastructural characteristics of the abnormal
interstitial cell population pointed towards renal involvement by a neoplastic dendritic cell process.
Renal Biopsy Diagnosis
Diffuse Atypical Histiocytic Interstitial Infiltrate, Favor Interdigitating Dendritic Cell Sarcoma (IDCS)
Differential Diagnosis and Discussion
Dendritic cells are a heterogenous group of immune presenting cells residing in lymphoid and non-
lymphoid tissue. The predominant sites for interdigitating dendritic cells are in the paracortex and deep
cortex of the lymph node, in the splenic arteriolar lymphoid sheaths and interfollicular areas of mucosa-
associated lymphoid tissue. Dendritic cell neoplasms have been classified by the International
Lymphoma Study Group (ILSG) into three immunophenotypic groups: Interdigitating dendritic cell
tumors/sarcomas (IDDCT/S), Follicular dendritic cell tumors/sarcomas (FDCT/S), and Langerhans’ cell
tumors/sarcomas (LCT/S). Interdigitating Dendritic Cell Sarcoma (IDCS) is a rare disease with less than
50 cases published in the world literature. IDCS usually presents with lymphadenopathy commonly in
cervical, axillary and inguinal lymph nodes (8, 10, 23, 25, 26, 27, 28). However, many extranodal sites
may be involved by IDCS. The most common extranodal sites reported in the literature are skin (7), oral
cavity (12, 13), tonsils (1), parotic gland (21), salivary gland (3), lung (19), chest wall (6, 16),
mediastinum (22), breast (24), spleen (9), liver (14), small and large intestine (14, 2), testis (11), bladder
(20), ovaries (19), bone (16), paravertebral space (16), and bone marrow (9).
IDCS usually occurs in adults, but has been reported to occur in patients as young as two years old (9,
16, 17, 18, 19). The patient age range is from 23 months to 87 years with an average age of 71 years.
There is a slight male predominance with a male to female ratio of 1.5:1. The clinical course may vary
from indolent behavior to occasional fatal disease (15).
Diagnosis of the IDCS relies on immunophenotypic and electron microscopic studies. Neoplastic
interdigitating dendritic cells constantly express S100 protein and vimentin. They have a variable
expression of histiocyte associated marker CD68 but are always negative for the Langerhans cells
marker CD1a. They do not express follicular dendritic cell antigens such as CD21 or CD 35. They have
variable expression for CD45 and lysozyme (LYS). In general, the immunohistochemistry marker panel
consisting of vimentin, S100, CD68, CD1a and CD35 together with ultrastructural assessment of nuclear
features, junctional components and presence of Birbeck granules can reliably differentiate the majority
of histiocytic/dendritic cell neoplasms (25).
Other morphologic mimics of IDSC such as spindle cell carcinoma or thymoma can be excluded by
cytokeratin staining. By EM, both IDCS and FDCS have complex interdigitating cytoplasmic extensions
and lack the ultrastructural features of myofibroblasts or fibroblasts, such as dense bodies, basal lamina
or abundant collagen. However, IDCS has no intercellular desmosomal junction like FDCS. Presence of
cytoplasmic organelles such as intermediate filaments, lysosomes, mitochondria and rough endoplasmic
reticulum, are variable. Rare cases of dendritic cell tumors baring both features of IDCS and FDCS or
histiocytic sarcoma and IDCS have been described (27, 28).
Most cases describing renal involvement by a neoplastic histiocytic process have been attributed to
either Histiocytosis X or Erdheim Chester disease, which is a rare form of non-Langerhans cell
histiocytosis. The most common clinical presentation of these patients is impaired renal function. In our
case, the peripheral eosinophilia and eosinophilic infiltrate among the tumor cells make the differential
diagnosis from Langerhans Cell Histiocytosis necessary, which was accomplished by demonstating the
lack of Birbeck granules by electron microscopy and lack of CD1a stain by IHC. Due to its rare
incidence the accurate diagnosis of IDCS is still challenging, especially when the tumor cells present
overlapping IHC features with other subtypes of dendritic cell neoplasms.
1. Androulaki A, Giaslakiotis K, Lazaris A, Br J Haematol. 2005 131(4):415
2. Banner G, Beauchamp ML, Liepman M, Interdigitating reticulum-cell sarcoma of the intestine: a case
report and review of the literature. Diagn Cytopathol 1997; 17:216–22.
3. Barwell N, Howatson R, Jackson R, et al. Interdigitating dendritic cell sarcoma of salivary gland associated
lymphoid tissue not associated with HHV-8 or EBV infection. J.Clin Pathol. 2004 ;57(1):87-9.
4. Chan W, Zaatari G, et al. Lymph node interdigitating reticulum cell sarcoma. Am J Clin Pathol 1986;
5. Dillon K, Hill C, Cameron C, et al. Mediastinal mixed dendritic cell sarcoma with hybrid features. Journal
of Clinical Pathology 2002;55:791-794
6. Gaertner E, Tsokos M, Derringer G, et al. Interdigitating dendritic cell sarcoma: a report of four cases and
review of the literature. Am J Clin Pathol 2001; 115:589–97
7. Hui P, Feller A, Kaiserling H, et al. Skin tumour of T accessory cells (interdigitating reticulum cells) with
high content of T lymphocytes. Am. J. Dermatopathol. 1987; 9; 129–137.
8. Jayaram G, Mun KS, Elsayed EM, et al. Interdigitating dendritic reticulum cell sarcoma: cytologic,
histologic and immunocytochemical features. Diagn Cytopathol. 2005; 33(1):43-8
9. Kawachi K, Nakatani Y, Inayama Y, et al. Interdigitating Dendritic Cell Sarcoma of the Spleen: Report of
a Case With a Review of the Literature. Am J Surg Pathol. 2002; 4 :530-537
10. Liu S, Huang P, Liu J, et al. Interdigitating reticulum cell tumor of lymph node: a case report and literature
review. Pathol Int 1998; 48:974–80.
11. Luk ISC, Shek TWH, Tang VWL, et al. Interdigitating dendritic cell tumor of the testis: a novel testicular
spindle cell neoplasm. Am J Surg Pathol 1999; 23:1141–8.
12. Marilia P, Trierveiler D, Martins G, et al. Dendritic cell sarcoma of the oral cavity Oral Oncology
2004, 40,(3 ): 341-347
13. Martins M, Witzel A, Sugaya N, et al. Dendritic cell sarcoma of the oral cavity.
Oral Oncol. 2004;40(3):341-7.
14. Mittinen M, Fletcher C, Lascota J, et al. True histiocytic lymphoma of small intestine: analysis of two S-
100-positive cases with features of interdigitating reticulum cells sarcoma. Am J Clin Pathol 1993;
15. Olnes M, Nicol T, et al. Interdigitating dendritic cell sarcoma: a rare malignancy responsive to ABVD
chemotherapy Leuk Lymphoma. 2002;43(4):817-21
16. Pillay K, Salomon R, et al. Interdigitating dendritic cell sarcoma: a report of four paediatric cases and
review of the literature. Histopathology. 2004;44(3):283-91.
17. Pileri A, Grogan T, Harris N, et al. Tumours of histiocytes and accessory;41(1):1-29
18. Porter D, Gupte G, Brown R, et al. Histiocytic sarcoma with interdigitating dendritic cell differentiation. J
Pediatr Hematol Oncol. 2004;26(12):827-30
19. Rabkin M, Kjeldsberg C, Hammond M, et al. Clinical, ultrastructural, immunohistochemical and DNA
content analysis of lymphomas having features of interdigitating reticulum cells. Cancer 1988; 61:1594–
20. Rupar G, Gale G, et al. Interdigitating dendritic cell sarcoma of urinary bladder mimicking large
intravesical calculus. 2005 Urology. Nov;66(5):1109.
21. Sharma M, Hsan F, et al. Interdigitating dendritic cell sarcoma of the parotid gland. J Laryngol Otol. 2005
22. Togashi K, Shinohara H, Isoda M, et al. Primary mediastinal lymph node malignancy with features
suggestive of dendritic cell sarcoma.
Jpn J Thorac Cardiovasc Surg. 2005; Jul 53(7):377-81
23. Turner R, Wood G, Beckstead J, et al. Histiocytic malignancies: morphologic, immunologic, and enzymatic
heterogeneity. Am J Surg Pathol 1984; 8:485–500
24. Uluoglu O, Ulner A, et al. Interdigitating dendritic cell tumor with breast and cervical lymph node
involvement: a case report and review of literature. Virchows Arch 2005; 446(5):546-54
25. van den Oord J, de Wolf-Peeters C, de Vos R, et al. Sarcoma arising from interdigitating reticulum cells:
report of a case, studied with light and electron microscopy, and enzyme- and immunohistochemistry.
Histopathology. 1986 May;10(5):509-23
26. Weiss L, Berry G, Dorfman R, et al. Spindle cell neoplasm of lymph nodes of probable reticulum cell
lineage: true reticulum cell sarcoma? Am J Surg Pathol 1990; 14:405–14
27. Yamakawa M, Matsuda M, Imai Y, et al. Lymph node interdigitating cell sarcoma. A case report. Am J
Clin Pathol. 1992 Jan;97(1):139-46.
28. Ylagan L, Bartlett N, Kraus M, et al. Interdigitating dendritic reticulum cell tumor of lymph nodes: case
report with differential diagnostic considerations. Diagn Cytopathol.2003 May;28(5):278-81
Glen S. Markowitz
A 55 year-old Caucasian woman presented to her primary care physician with progressive
fatigue for several months, dyspnea with minimal exertion, loss of appetite, 15 pound weight
loss, and recurrent low-grade fevers. Past medical history was significant only for migraine
headaches. The patient was taking no prescription or over-the-counter medications. There was
no history of environmental toxin exposure, recent travel, smoking, excess alcohol
consumption, or use of illicit drugs. She was empirically treated with esomeprazole and
amoxicillin, but returned two weeks later reporting no improvement in her symptoms.
Laboratory studies revealed anemia, thrombocytopenia, hypercalcemia, and acute renal
failure. The patient was admitted for further evaluation.
Upon admission, physical examination revealed a well-nourished but pale female with a BP of
156/70 mmHg, pulse 96 bpm, temperature 98.6 F, and respiratory rate 20 breaths/min.
Cardiac and pulmonary examinations were unremarkable. Abdominal exam revealed
splenomegaly with a palpable liver edge. Laboratory testing was notable for a hemoglobin of
6.1 g/dl (nl 11.0–15.0 g/dl), platelet count 112 K/mm3 (nl 150–400 K/mm3), creatinine 3.7
mg/dl, calcium 12.4 mg/dl (nl 8.5–10.1 mg/dl), 1,25 Vitamin D 91.3 pg/ml (nl 15.9-55.6
pg/ml), and albumin 2.9 g/dl (nl 3.4–5.0 g/dl). Liver function tests, coagulation studies, and
parathyroid hormone level were normal. Urinalysis revealed 1+ protein, 1+ glucose, and trace
blood. The following serologies were negative or normal: C3, C4, anti-GBM antibody, PR3-
ANCA, and MPO-ANCA. Serum protein electrophoresis (SPEP) with immunofixation showed
no monoclonal protein. Bone marrow biopsy revealed normocellular marrow without
evidence of lymphoma or plasma cell dyscrasia. A non-contrast CT scan of the chest,
abdomen, and pelvis was notable for splenomegaly (18 x 15 x 10 cm) with a hypodense area
measuring 7 x 7 x 4 cm and mild hepatomegaly. The kidneys measured 11.7 and 12 cm in
length by ultrasound, without evidence of obstruction. A skeletal survey showed no
The patient was treated with hydration and a single dose of pamidronate. At the time of
discharge 6 days later, her creatinine had fallen to 1.9 mg/dl and her calcium had normalized.
Following discharge, she was scheduled for nephrology consultation.
The patient was seen in nephrologic consultation one week following discharge, at which time
her creatinine had declined to 1.5 mg/dl. In light of the absence of a clear indication for the
splenomegaly or persistent renal dysfunction, renal biopsy was performed.
Renal Biopsy Findings:
Sampling for light microscopy included two cores of renal cortex containing 14 glomeruli, one
of which was globally sclerotic. Glomeruli appeared histologically unremarkable. Proximal
tubules displayed mild degenerative changes characterized by luminal ectasia, cytoplasmic
simplification with vacuolization, and prominent nucleoli. The degenerative changes in
proximal tubules were accompanied by intracellular inclusions which appeared pale with the
H&E and PAS stains and multifocally formed cleft-like spaces. There was mild interstitial
inflammation composed of mainly lymphocytes and rare foci of mild tubulitis. There was
moderate tubular atrophy and interstitial fibrosis involving approximately 40% of the cortex
sampled. Vessels exhibited mild arteriosclerosis. Congo red staining for amyloid was negative.
Sampling for immunofluorescence consisted of 5 glomeruli and exhibited no significant
glomerular positivity for IgG, IgM, IgA, C3, C1, fibrinogen, albumin, or kappa or lambda light
chains. There were rare tubular casts which stained similarly for IgA, kappa, and lambda.
After review of the ultrastructural findings, immunoflourescence staining was repeated
following pronase-digestion and revealed intracellular needle-shaped crystals in proximal
tubules which stain positive for kappa and negative for lambda.
The predominant abnormalities seen on ultrastructural evaluation involved the proximal
tubules. In addition to tubular degenerative changes, proximal tubules contained abundant
intracellular and focal intraluminal crystalline inclusions. The inclusions had a fibrillar
appearance, formed parallel arrays, and did not appear to be membrane-bound. Glomeruli
exhibited no significant ultrastructural abnormalities.
Renal biopsy diagnosis:
Light chain proximal tubulopathy, kappa-type
(a.k.a. Light chain Fanconi syndrome; LCFS)
Clinical Follow-up #1:
Following receipt of the renal biopsy results, serum free light chain testing was performed and
showed a normal kappa/lambda ratio of 0.9. Urine protein electrophoresis with
immunofixation showed a monoclonal kappa Bence Jones protein. LCFS is mainly associated
with multiple myeloma, which does not typically involve the spleen. Nonetheless, in light of
the monoclonal urine spike and renal biopsy findings, splenectomy was performed.
Due to direct extension of the splenic mass into the distal pancreas, combined splenectomy
with distal pancreatectomy was performed. Grossly, the splenic parenchyma was almost
entirely replaced by a yellow-grey soft mass with a necrotic center.
Microscopic evaluation of the splenic and distal pancreatic mass showed a diffuse, dense
sheet-like infiltrate of pleomorphic medium- to large-sized lymphocytes and zones of
coagulative necrosis. The lymphocytes exhibited round to ovoid vesicular nuclei with
multiple small or single prominent nucleoli. In a few areas, the lymphocytes showed
plasmacytoid morphology. The neoplastic cells expressed CD20, Pax-5, and CD79a (B-cell
markers), BCL2, and subsets showed either BCL6 or MUM1 expression (markers of germinal
center B-cells and activated lymphocytes or plasma cells, respectively). The cells showed a
high proliferation index (80%) on staining for Ki-67/MIB1, and did not express CD3 or CD5
(T-cell markers), CD10, CD23, CD138 (a mature plasma cell marker), or CD43. In situ
hybridization for immunoglobulin light chain mRNA showed cytoplasmic kappa light chain
restriction. No EBER positive cells were seen by in situ hybridization. The morphology and
phenotype were consistent with a diffuse large B-cell lymphoma (DLBCL), “activated” or non-
germinal center type.
Diffuse large B-cell lymphoma with plasmacytoid differentiation and kappa light chain
Clinical Follow-up #2:
Following splenectomy, the patient’s creatinine declined over 4 days from 1.6 to 1.2 mg/dl.
Over the following three weeks, the creatinine declined further to 0.8 mg/dl, at which point
the patient began chemotherapy. Four months later, following 6 cycles of chemotherapy with
CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) and Rituximab, the
patient has a creatinine of 1.0 mg/dl.
Light chain proximal tubulopathy, more commonly referred to as light chain Fanconi
syndrome (LCFS), is a rare pattern of renal disease that occurs in the setting of dysproteinemia.
LCFS shares similarities with the more common entity of myeloma cast nephropathy (MCN) in
that both conditions are characterized by tubular injury with crystalline deposits of
monoclonal light chains. In LCFS, the crystalline deposits are intracellular and confined to
proximal tubules, as opposed to the intraluminal, distal tubular casts seen in MCN.1 As a
result of crystal accumulation in proximal tubules, patients with LCFS exhibit features of
Fanconi syndrome (i.e. proximal tubular dysfunction), including normoglycemic glycosuria,
aminoaciduria, uricosuria, hyperphosphaturia (with hypophosphatemia), and type II renal
tubular acidosis. In the case reported herein, testing for Fanconi syndrome was not performed
although the patient was noted to have normoglycemic glycosuria.
Light chain Fanconi syndrome often is a difficult diagnosis to establish based on limited
awareness of the entity, its relatively indolent presentation in the majority of cases, and the
subtle light microscopic findings. Light microscopy typically reveals non-specific findings of
acute and chronic tubulointerstitial scarring. The cytoplasm of proximal tubules contains pale
needle-shaped crystals that are mainly visible at high power and may have a relatively
localized distribution. The crystals typically appear pale with the hematoxylin & eosin and
periodic acid Schiff stains, and often do not stain for kappa or lambda light chain by standard
immunofluorescence (IF) on frozen tissue. As a result, the diagnosis of LCFS may not be
appreciated until ultrastructural evaluation, at which time abundant crystals of varying
appearance are identified within the cytoplasm of proximal tubules. Interestingly, IF on
formalin-fixed, paraffin-embedded, pronase-digested tissue appears to be superior to standard
IF performed on frozen tissue for determining the light chain composition tubular crystals and
establishing the diagnosis of LCFS.2 This may relate to the fact that pronase digestion has a
denaturing effect on cell membranes which may unveil sequestered antigenic sites.
LCFS is a rare renal disease with fewer than 100 cases appearing in the medical literature,
predominantly reported as isolated cases and small series. In 1975, Maldonado et al. provided
the first large series of LCFS, presenting 3 new cases from the Mayo Clinic and reviewing the
findings in 14 previously published cases.3 In this initial description, common characteristics
included relatively indolent renal dysfunction, Bence Jones proteinuria of kappa-type, and in
some cases, osteomalacia resulting from chronic hypophosphatemia. Of note, in 11 of the 17
cases LCFS were discovered prior to the development of multiple myeloma (MM) or, less
commonly, amyloidosis. In the remaining 6 patients, the diagnosis of LCFS and MM or
amyloidosis was established simultaneously, leading the authors to suggest that LCFS
represents a precursor to MM. In 2000, Messiaen et al. detailed 11 cases of LCFS and
emphasized the clinical heterogeneity of this entity.4 In this series, clinical presentations
ranged from acute renal failure to more indolent renal dysfunction, and multiple patients came
to clinical attention for bone pain related to lytic lesions of MM.
Features of proximal tubular dysfunction were identified in all 11 patients. In 2007, Kapur et
al. published a report of 5 cases of LCFS but broadened the definition to include 3 cases in
which electron microscopy (EM) only revealed prominent phagolysosomes within tubular
epithelia, which subsequently were found to contain kappa light chains by immune-EM. 5
Fanconi syndrome is uncommon in adults and most often signifies the presence of a plasma
cell dyscrasia. A clinical diagnosis of FS or a pathologic diagnosis of LCFS should prompt a
thorough hematologic work-up that may include SPEP, UPEP, serum free light chain testing,
bone marrow biopsy, and skeletal survey. The vast majority of reported cases of LCFS have
occurred in patients who have evidence of or later develop MM or, less commonly,
amyloidosis. There are also rare reports of patients with LCFS in the setting of chronic
lymphocytic leukemia/small lymphocytic lymphoma.6,7 In the case reported herein, LCFS was
the result of kappa light chain production by a large splenic mass of DLBCL. To our
knowledge, this is the first report of DLBCL causing LCFS.
The propensity for the light chains in LCFS to form crystals that precipitate within the
cytoplasm of proximal tubules appears to be determined by the amino acid sequences and
resultant physical and chemical properties. In the normal state, light chains pass through the
GBM and are reabsorbed by the proximal tubule where they are broken down to amino acids
by lysosomal enzymes. The first reported characterization of a monoclonal kappa-cDNA from
a patient with LCFS was published by Aucouturier et al. in 1993. Sequencing of the kappa-
cDNA showed that the variable region exons most closely fit into the VK1 subgroup. Protease
treatment of the light chain produced an elongated NH2-terminal fragment of the variable (V)
domain which was resistant to further degradation and was able to form crystals when bound
to itself or intact kappa light chains. It was hypothesized that the unique properties of this
VK1 subgroup light chain, namely its resistance to complete proteolysis and its ability to form
crystals, might explain the proximal tubular crystal formation and FS seen in patients with
LCFS.8 A subsequent study by the same group compared the protease resistance of light
chains from 4 patients with LCFS to 12 patients with MCN. In all 4 patients with LCFS, the
light chains were of the VK1 subtype and were partially resistant to proteolysis, producing a
12 kDa NH2-terminal fragment that was not further degraded by pepsin or cathepsin B, which
are principle proteolytic lysosomal enzymes of the proximal tubules. In contrast, the light
chains from 12 patients with MCN were susceptible to proteolytic digestion.9 Based on these
studies, the capacity to develop LCFS appears to be 1) intrinsic to the light chain molecule; 2)
genetically determined as evidenced by common origin from the VK1 subgroup; and 3) based
on a physical property of partial resistance to proteolysis, leading to the formation of a
truncated NH2-terminal fragment with a propensity to crystallize. Analogous mechanisms of
proteolytic resistance and crystal formation are likely to underlie the infrequent cases of LCFS
associated with lambda light chain production.6,10
In 2006, Sirac et al. published a transgenic murine model of LCFS which supported many of
the existing concepts on the pathogenesis of this condition.11 In this model, the mouse JK
region was replaced by the VK-JK gene from a patient with LCFS. The mice developed LCFS
with proximal tubular crystals that appeared similar to what has been described in the human
condition, supporting the concept that the development of LCFS is determined by the amino
acid sequence and resultant physicochemical properties of the monoclonal light chain. When
the human VK-JK expression was conditionally deleted, tubular crystal formation was
Prognosis and optimal therapy for LCFS remain largely unknown. While the majority of
patients have slowly progressive renal dysfunction, more precipitous development of ARF
infrequently occurs. In the series of 11 patients reported by Messiaen et al., 4 patients reached
the endpoint of doubling of creatinine or requirement for dialysis.4 In 2004, Ma et al. reported
the Mayo Clinic experience with adult-acquired FS.12 Over a 35 year period, 32 patients were
seen including 10 with MM, 6 with smoldering MM, 2 with Waldenstrom’s
macroglobulinemia (WMG), and 14 with MGUS. The mean creatinine in this cohort was 2.0
mg/dl, all patients had evidence of light chain Bence Jones proteinuria (29 kappa; 3 lambda),
and 69% had a monoclonal serum protein. Importantly, only 17 patients underwent renal
biopsy, among which only 8 had crystals in proximal tubular cells characteristic of LCFS. Thus,
the data from this cohort is reflective of a heterogeneous group that is not limited to
individuals with LCFS. Nonetheless, the findings are noteworthy. Over the period of follow-
up (mean 65 months), 5 patients progressed to ESRD, which in each instance was more than 7
years following initial diagnosis of FS. The median time from diagnosis of FS to ESRD was 196
months, and only 1 of 10 patients with MGUS evolved to MM. Chemotherapy was given to all
patients with MM or WMG, 4 of 6 patients with smoldering MM, and 6 of 14 patients with
MGUS. Among the 10 patients with smoldering MM or MGUS who received chemotherapy,
no significant improvement in renal function was seen over 4-26 months of treatment.
Importantly, 4 patients (1 MGUS, 1 smoldering MM, 2 MM) developed treatment-related
myelodysplastic syndrome or acute leukemia and died. The authors concluded that adult-
acquired FS has a slow progression to ESRD and that the risk of chemotherapy with alkylating
agents appears unjustified in patients who lack evidence of overt malignancy.
In summary, LCFS is a rare disease characterized by slowly progressive renal dysfunction
associated with FS. The diagnosis of LCFS requires pathologic evaluation, where the
distinctive finding is accumulation of crystalline inclusions composed of light chains within
the cytoplasm of proximal tubules. The monoclonal light chains are typically of kappa type
and are derived from the VK1 subgroup. These light chains have the properties of resistance to
proteolysis within proximal tubules and a propensity to form intracellular crystals. Patients
with LCFS typically have evidence of MM, “smoldering MM”, or MGUS, although rarely this
condition may be associated with B cell non-Hodgkin lymphoma. In cases of LCFS with
malignancy such as the one reported here, long-term prognosis is likely to be closely tied to
success in treating the underlying malignancy.
1 Markowitz GS. Dysproteinemia and the kidney. Adv Anat Pathol 2004; 11:49-63.
2 Nasr SH, Galgano SJ, Markowitz GS et.al. Immunofluorescence on pronase-digested paraffin
sections: A valuable salvage technique for renal biopsies. Kidney Int, 2006; 70: 2148-2151.
3 Maldonado JE, Velosa JA, Kyle RA et.al. Fanconi syndrome in adults: A manifestation of a latent
form of myeloma. Am J Med, 1975; 58:354-364.
4 Messiaen T, Deret S, Mougenot B et.al. Adult Fanconi syndrome secondary to light chain
gammopathy: Clinicopathologic heterogeneity and unusual features in 11 patients. Medicine,
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5 Kapur U, Barton K, Fresco R et.al. Expanding the pathologic spectrum of immunoglobulin light
chain proximal tubulopathy. Arch Pathol Lab Med, 2007; 131:1368-1372.
6 Thorner PS, Bedard YC, Fernandes BJ. Lambda-light-chain nephropathy with Fanoconi’s
syndrome. Arch Pathol Lab Med, 1983; 107: 654-657.
7 Rao DS, Parfitt AM, Villanueva AR et.al. Hypophosphatemic Osteomalacia and Adult Fanconi
Syndrome due to light-chain nephropathy. Am J Med, 1987; 82: 333-338.
8 Aucouturier P, Bauwens M, Khamlichi AA et.al. Monoclonal Ig L chain and L chain V domain
fragment crystallization in myeloma-associated Fanconi’s syndrome. J Immunol, 1993; 150: 3561-
9 Leboulleux M, Lelongt B, Mougenot B et.al. Protease resistance and binding of Ig light chains in
myeloma-associated tubulopathies. Kidney Int, 1995; 48: 72-79.
10 Rikitake O, Sakemi T, Yoshikawa Y et.al. Adult Fanconi syndrome in primary amyloidosis with
lambda light chain proteinuria. Jpn J Med, 1989; 28: 523-526.
11 Sirac C, Bridoux F, Carrion C et.al. Role of the monoclonal K chain V domain and reversibility of
renal damage in a transgenic model of acquired Fanconi syndrome. Blood, 2006; 108: 536-543.
12 Ma CX, Lacy MQ, Rompala JF et.al. Acquired Fanconi syndrome is an indolent disorder in the
absence of overt multiple myeloma. Blood, 2004; 104: 40-42.
Anthony M Dorman
Beaumont Hospital, Dublin
Royal College of Surgeons in Ireland
A 73-year old lady is referred to a Nephrologist by her primary care physician with a rising
creatinine. Her creatinine was determined as normal seven months previously. It is now 1.8mg/dl on
referral. Eight months previously she was diagnosed with M.G.U.S. – IgA Lambda. The specific
features of this monoclonal gammopathy were a total protein of 83gms/l. (60-80). She had a
monoclonal paraprotein band of more than 15g/L. Her IgA was 10.3g/L.(0.62-2.90). She also had
slight Bence-Jones proteinuria. Her family history is of interest in that her two siblings both have
been diagnosed with multiple myeloma. Her brother died of renal amyloidosis several years ago.
The details of his myeloma are not available. Her sister has an IgG Lambda myeloma and is alive
with systemic amyloidosis.
Her past medical history shows the presence of hypertension which is controlled by Verapimal. She
has a history of atrial fibrillation associated with minimal coronary artery disease of one year
duration. The atrial fibrillation is associated with anxiety and depression. She is being treated for the
latter with Warfarin and Anxiolytic drugs. She has a history of asthma and chronic obstructive
pulmonary disease and has mild hypothyroidism. She has a history of four pregnancies, all delivered
by caesarean section but otherwise uncomplicated. She is not a smoker and has never consumed
On clinical examination she is a thin lady. Examination of the cardiovascular system confirms the
presence of atrial fibrillation. She is normotensive. Urinalysis is positive for blood and protein.
On investigation the positive findings were as follows: monoclonal gammopathy of uncertain
significance which is IgA Lambda. She has mild Bence-Jones proteinuria. Haemoglobin is 11.7g/dl.
It is microcytic and hypochromic. Chemical pathology investigations show a GGT of 99 units/litre
(6-42). Urea is 15.1mmol/L (3.4-8.0). Creatinine is 1.8mg/dl. Estimated GFR is 21ml/min. (60-104).
ALP is 152U/L. (35-104). A bone marrow trephine shows 1% plasma cells with occasional bi-
nucleate forms. A skeletal survey is negative for the presence of lytic lesions. Her medications are
Mirtazapine and Benzodiazepine for anxiety. Arthritic symptoms are treated with Diclofenac, a
steroid and beta 2 antagonist inhaler for asthma and Verapamil for hypertension.
The indications for renal biopsy which ensued were hypertension which was controlled by
Verapamil, proteinuria in a non-nephrotic range of 1-2g/24hours, microscopic haematuria and a
creatinine of 1.8mg/dl.
Renal Biopsy Findings
The biopsy was performed 150 miles from the laboratory and tissue for fluorescence microscopy
was submitted in Michel’s transport medium. Tissue was also submitted in formalin for light
microscopy and a small piece of tissue in glutaraldehyde for electron microscopy.
The tissue submitted for fluorescence microscopy showed the presence of eleven (11) glomeruli,
three (3) of which were sclerosed. It was noted that the frozen section showed arteries with mild to
moderate sclerosis. The non-sclerosed glomeruli were negative for C3, C4, IgA, IgG, IgM,
Fibrinogen, Kappa and Lambda. The tissue submitted for light microscopy yielded three cores of
renal cortex and medulla with eighty seven (87) glomeruli. Forty three (43) of the eighty seven (87)
glomeruli were sclerosed. The remainder show mild focal periglomerular fibrosis and contained
occasional capillary loops with thickening and double contour formation. While the tubules show
focal fibrosis and some hyaline casts the latter showed no features of myeloma kidney. Fibrosis
involves 35% of the cortex approximately and is associated with mild chronic inflammation.
Arteries show mild to moderate sclerosis, predominantly of fibrous intimal proliferation type.
Arterioles show focal mild, moderate and severe occlusive hyaline sclerosis. Many normal arterioles
are also present.
Two blocks were prepared from the tissue sent for electron microscopy with neither containing any
glomeruli for examination. Because of this glomeruli were retrieved from the paraffin wax
embedded tissue and submitted for electron microscopy. Two glomeruli were analysed from this
tissue and showed endothelial organising inflammation, including fluffy material and inflammatory
debris in a subendothelial location. This is in areas associated with new membrane formation. No
immune complex deposits, features of light chain deposition disease or amyloid fibrils were present.
Renal Biopsy Diagnosis
1. Chronic thrombotic angiopathy (TMA).
(a) arteriosclerosis – fibrous intimal type – focally moderate to severe
(b) arteriolarsclerosis – focally mild, moderate and severe occlusive
(c) glomerular double contours
Eight months following her renal biopsy her clinical condition continued to be much the same as
when seen at presentation. She continued to have some chronic aches and pains but has no new
symptoms suggestive of progression to myeloma. Her full blood count shows continued mild
anaemia with a haemoglobin of 11.3g/dl with a normal white cell count and normal platelet count.
Her renal function is relatively stable with a serum creatinine of 1.75mg/dl. Her last serum para-
protein showed a further increase to 21g/L but her serum free light chains were normal. She is being
maintained on Verapamil and Lasix for hypertension, Mirtazapine and Benzodiazepine for anxiety
attacks, Diclofenac for generalised aches and pains and steroid and beta two antagonist inhaler for
asthma. Because she has an IgA MGUS with a monoclonal band of >15g/L it is considered that she
has an estimated risk of 37% over a twenty year period of developing multiple myeloma.
This is a 74-year old female presenting with monoclonal gammopathy of uncertain significance with
a strong family history of multiple myeloma. Familial plasma cell dyscrasia including monoclonal
gammopathy and multiple myeloma are well described.1,2,3 Prior to her diagnosis of monoclonal
gammopathy her renal function is normal. Her renal function begins to deteriorate one month
following her diagnosis and she presents to her Nephrologist seven months following her initial
diagnosis and has a renal biopsy performed. The renal biopsy shows subtle but distinct features of
chronic thrombotic microangiopathy, most characteristically identified on electron microscopy. The
features identified on the renal biopsy could to some extent be explained by her history of
hypertension. In addition, despite the absence of clinical complications some of them could also be
related to her pregnancies. There does however seem to be a clear clinical and chronological
correlation between her diagnosis of monoclonal gammopathy and the development of renal function
impairment. Chronic thrombotic microangiopathy is a non-specific histopathological pattern of
injury. It is not a specific diagnosis in itself. There are many causes and associations.4 These include:
drugs, infections, pregnancy, auto-immune disease, neoplasia and malignant hypertension. Drugs
include cyclosporin A, Tacrolimus, Statins, Clopidogrel, Quinine, chemotherapeutic agents and
many others. Autoimmune diseases include lupus anticoagulant, anti-phospholipid antibody
syndrome, scleroderma and rheumatoid arthritis. Infections include E.coli 0157 with classic
haemolytic syndrome, pneumococcus, antrax, Rocky Mountain spotted fever and many others.
POEMS syndrome is a multi-systemic syndrome associated with plasma cells dyscrasia where the
polyneuropathy component of the syndrome is attributed to central nervous system thrombotic
microangiopathy. Renal involvement in POEMS syndrome is relatively uncommon but is well
described. There is also an increase in literature of thrombotic microangiopathy described involving
the kidney in plasma cell dyscrasia. The traditionally described renal lesions associated with plasma
cell dyscrasia include cast nephropathy, infiltrative or deposition diseases, effects of hypercalcaemia
and crystal storage in histiocytosis or monoclonal light chain crystals in renal proximal tubular cells.
The infiltrative and deposition diseases include AL amyloidosis, light chain deposition disease, light
and heavy chain deposition disease, heavy chain deposition disease and others including
cryoglobulinaemia and micro tubule or fibrillary depositions and infiltrations.5,6 Thrombotic
microangiopathy should also be added to this list. While serum and vascular endothelial growth
factor (VEGF) has been implicated in causing or being associated with thrombotic angiopathy in
POEMS syndrome, it is possible that this is a down-stream effect and the specific cause of
thrombotic microangiopathy in plasma cell dyscrasia is uncertain.7
Patterns of chronic vascular injury
Arteries as seen in renal biopsies may show a variety of patterns of injury. The term
“arteriosclerosis” is non-specific and can include atherosclerosis, myxoid medial degeneration,
vasculitis, athero-embolic disease and chronic thrombotic microangiopathy. Myxoid medial
degeneration may be primary as seen in Marfan’s syndrome or secondary to other causes of
arteriosclerosis. Organised vasculitis as seen, for example, ANCA-vasculitis will show a different
pattern of injury. Athero-embolic lesions are readily identified by the presence of cholesterol clefts.
Chronic thrombotic microangiopathy is characterised by fibrous intimal proliferation on the luminal
side of the internal elastic lamina with relative preservation of the muscle wall of the vessel. Stains
for elastin can be very useful in distinguishing these different patterns of arterial injury.
Arteriolar sclerosis can also show different patterns of injury. It may be hyaline and mural. The latter
may be nodular as seen in transplant biopsies, i.e. associated with chronic calcineurin inhibitor
It may be circumferential as seen in hypertension or diabetes mellitus (the latter in apparent and
efferent arterioles).8 There may also be occlusive hyaline lesions as seen in organised chronic
thrombotic lesions. These may also show an “onion skin”- like appearance during the organisation
phase or may be characterised by the presence of hyaline “plugs” occluding the lumen. PAS stain is
very useful in distinguishing these patterns of arteriolar injury.
Plasma cell dyscrasia may be associated with renal thrombotic microangiopathy, in particular
chronic thrombotic microangiopathy, as well as the classically described renal manifestations of
plasma cell dyscrasia and multiple myeloma. The features of chronic thrombotic microangiopathy
may be subtle and show features that are attributed often to non-specific arteriosclerosis or
longstanding hypertension. The application of special stains and electron microscopy as in this case
is often very useful in identifying endothelial lesions in blood vessels and glomeruli to a thrombotic
microangiopathic pattern of injury.
1. Lynch HT, Ferrara K, Barlogie B, et al. Familial Myeloma. N Engl J Med 2008;359(2):152-7.
2. Lynch HT, Sanger WG, Pirruccello S, et al. Familial Multiple Myeloma: a Family Study and
Review of the Literature. J Natl Cancer Inst 2001; 93 (19): 1479-83.
3. Tsai HM, Advances in the Pathogenesis, Diagnosis, and Treatment of Thrombotic
Thrombocytopenic Purpura. J Am Soc Nephrol 2003; 14: 1072-1081.
4. Kanjanabuch T, Bunruang R, Srisawat N, et al. The Combination of thrombotic
microangiopathy and nodular sclerosis in light chain deposition disease. J Med Assoc Thai
2006; 89 Suppl 2:5248-52.
5. Herrera GA, Joseph L, Gu X et al. Renal pathologic spectrum in an autopsy series of patients
with plasma cell dyscrasia. Arch Pathol Lab Med 2004; 128 (8); 875-9.
6. Herrera GA. The contributions of electron microscopy to the understanding and diagnosis of
plasma cell dyscrasia-related renal lesions.
7. Soubrier M, Sauron C, Souweine B et al. Growth factors and proinflammatory cytokines in the
renal involvement of POEMS syndrome. Am J Kidney Dis 1999; 34 (4): 633-8.
8. Hughson MD and Lajoie G. Vascular diseases in “Renal biopsy interpretation”. Silva FG,
D’Agati VD and Nadasdy T (Eds) Chapter 12 (333-353).