Chapter 7: Hematologic Disorders and Kidney Disease
Ala Abudayyeh, MD,* and Kevin Finkel, MD, FACP, FASN, FCCM*†
*Division of General Internal Medicine, Section of Nephrology, University of Texas MD Anderson Cancer Center,
Houston, Texas; and †UTHealth Science Center at Houston Medical School, Department of Medicine, Division of
Renal Diseases and Hypertension, Houston, Texas
MULIPLE MYELOMA
Pathogenesis
Multiple myeloma (MM) is a hematologic malig-
nancy involving the pathologic proliferation of
terminally differentiated plasma cells. It is the
second most common hematologic malignancy
behind non-Hodgkin lymphoma, with an annual
incidence of 4–7 cases per 100,000 in the United
States. Clinical symptoms are due to osteolysis of
the bone, suppression of normal hematopoiesis,
and the overproduction of monoclonal immuno-
globulins that deposit in organ tissues. Clinical
symptoms include bone pain and fractures, anemia,
infections, hypercalcemia, edema, heart failure, and
renal disease.
Kidney involvement and pathology
More than one-half of patients with MM initially
present with varying degrees of AKI. Nearly 20%
of patients present with a serum creatinine .2.0
mg/dL, and 10% of patients require dialysis on
presentation (1). AKI is associated with higher
mortality, but this may be reflective of patients
with more advanced disease (2).
The major diseases in the spectrum of myeloma-
related kidney disease include cast nephropathy, light
chain deposition disease (LCDD), and AL-amyloidosis.
Renal biopsy demonstrates the presence of mono-
typic light chains on immunofluorescence exam, as
well as characteristic ultrastructural features of
deposits on electron microscopy. Less common
forms of renal injury include light chain–induced
Fanconi syndrome, cryoglobulinemia, prolifera-
tive glomerulonephritis, heavy chain deposition
disease, and immunotactoid glomerulonephritis
(Table 1) (3).3
Cast nephropathy
Cast nephropathy has been diagnosed in 41% of
patients with MM and renal disease (4). Excess light
American Society of Nephrology
chains precipitate with Tamm-Horsfall protein
(THP) secreted by the thick ascending limb of the
loop of Henle and produce casts in the distal tubule.
Decreased GFR may increase the concentration of
light chains in the distal tubule and enhance the
formation of casts. Therefore, hypercalcemia, vol-
ume depletion, diuretics, and nonsteroidal anti-
inflammatory drugs can exacerbate renal injury.
In some cases of AKI associated with MM, cast
formation is rare on renal biopsy. Instead, renal
injury is attributed to the direct toxic effects of
urinary free light chains (FLCs) on proximal tubule
cells (5,6). After reabsorption, lysosomal degrada-
tion of FLCs can activate the NF-kB pathway lead-
ing to oxidative stress with an inflammatory
response, apoptosis, and fibrosis. This lesion is
characterized histologically by loss of brush border
and cell vacuolization and necrosis (7).
The classic presentation is an elderly patient with
unexplained renal failure, anemia, and bone pain
or fractures. Proteinuria, when quantitatively mea-
sured with a 24-hour urine collection, is usually
subnephrotic and primarily composed of mono-
clonal light chains (Bence-Jones proteins). The
qualitative measurement of proteinuria using a
urine test strip, which mainly detects albumin, is
generally minimally reactive.
Most patients with myeloma cast nephropathy
are diagnosed without kidney biopsy using serum
and urine immunofixation and serum FLC analysis
(see Chapter 9). When biopsied, casts are eosin
positive, fractured, and waxy in appearance on light
microscopy (Figure 1) (8). Multinucleated giant
cells may surround casts, and an interstitial
Correspondence: Kevin W. Finkel, MD, FACP, FASN, FCCM,
Division of Renal Diseases & Hypertension, UTHealth Science
Center at Houston-McGovern Medical School, 6431 Fannin St.,
Houston, Texas 77030. Email: kevin.w.finkel@uth.tmc.edu
Copyright © 2016 by the American Society of Nephrology
Onco-Nephrology Curriculum 1
Table 1. Kidney manifestations of multiple myeloma
Myeloma cast nephropathy
AL amyloidosis
Light chain deposition disease
Heavy chain deposition disease
Immunotactoid glomerulopathy
Fibrillary glomerulopathy
Light chain Fanconi syndrome
Plasma cell infiltration
Cryoglobulinemia
Membranoproliferative glomerulonephritis
Membranous glomerulonephritis
inflammatory infiltrate composed of lymphocytes and mono-
cytes may also be present. Widespread tubular atrophy and
interstitial fibrosis eventually develops. Immunofluorescence
staining generally demonstrates light chain restriction within
the casts, although patterns may be mixed or nondiagnostic as
well. Casts have a lattice-like appearance and may contain
needle-shaped crystals on electron microscopy. The glomeruli
and vessels appear normal, unless LCDD is concurrently pre-
sent.
Light chain deposition disease
LCDD has been diagnosed at autopsy in 19% of patients with
MM and renal disease (4). The renal manifestations are most
apparent clinically, whereas light chain deposits within the
heart, liver, spleen, and peripheral nervous system may remain
asymptomatic. The hallmark of the disease is the development
of mesangial nodules from mesangial matrix expansion
secondary to the up-regulation of platelet derived growth
factor-b and transforming growth factor-b. The nodules can
occasionally be confused with the Kimmestiel-Wilson lesion
of diabetic nephropathy.
Clinically, patients present with proteinuria, renal insuf-
ficiency, and a nodular sclerosing glomerulopathy. Several
retrospective reviews have reported on the clinical character-
istics of these patients (9,10). The mean age was 58 years with
no significant preference with respect to sex. Marked renal
insufficiency was common on presentation, with a median
serum creatinine .4 mg/dL, and renal function rapidly de-
clined thereafter. Nephrotic range proteinuria was detected
in 26%–40% of patients and correlated with the degree of
glomerular involvement. Hypertension and microscopic he-
maturia were also present in the majority of patients.
Light chain deposition stimulates mesangial and matrix
expansion leading to nodule formation. On light microscopy,
mesangial nodules are more uniform in distribution and size in
LCDD compared with diabetic nephropathy (Figure 2) (8).
Irregular thickening and double contours of the glomerular
basement membrane may also be present. Eosin-positive de-
posits may be seen diffusely throughout the tubular basement
membranes. Immunofluorescence demonstrates a character-
istic linear staining of basement membranes with monotypic

Figure 1. Pathology of myeloma cast nephropathy. (A) Large atypical casts are seen within distal tubular lumina. The casts appear
hypereosinophilic with fractured texture and sharp edges. They are associated with giant cell (arrows) and mononuclear cell reaction,
acute proximal tubular cell injury, and interstitial inflammation (hematoxylin and eosin, 3,2003). (B) The casts characteristically are
periodic acid–Schiff (PAS) negative (3,2003). (C) Myeloma casts almost always stain for just k or l light chain. This figure shows bright
staining of casts for k (immunofluorescence, 3,4003). The casts were negative for l (data not shown). (D) Occasionally, myeloma casts
are composed of small rod- or needle-shaped crystals that fill the distal tubular lumina and, as shown, appear highly electron dense on
electron microscopy (31,8503). Reprinted from reference 8, with permission of the Elsevier Science and Technology Journals.

2 Onco-Nephrology Curriculum American Society of Nephrology

Figure 2. Pathology of light-chain proximal tubulopathy. (A) Large rod- and rhomboid-shaped hypereosinophilic crystals are seen
within proximal tubular cells. (hematoxylin and eosin, 3,6003). (B) In this patient with smoldering myeloma who has 20% k-restricted
plasma cells in the bone marrow, the proximal tubular crystals stain strongly for k (as shown) with negative l (not shown) by immu-
nofluorescence performed on pronase-digested, paraffin-embedded tissue. The intracellular crystals failed to stain for k or l on
standard immunofluorescence on frozen tissue (not shown; 3,4003). (C) Ultrastructurally, the proximal tubular cells are filled with
electron-dense light-chain crystals with rod, rhomboid, or rectangular shapes. The proximal tubule brush border appears preserved
(31,8503). (D) In this case of light-chain proximal tubulopathy, the proximal tubular cells are loaded with large election-dense
phagolysosomes without crystals (electron microscopy, 32,5003). Reprinted from reference 8, with permission of the Elsevier Science
and Technology Journals.

light chains, which are most commonly k restricted. On elec-
tron microscopy, granular-powdery deposits are distributed
within the mesangium and midportion of the glomerular,
tubular, and vessel wall basement membranes.
Therapy of LCDD is directed at the underlying myeloma.
Cytotoxic chemotherapy followed by hematopoietic stem cell
transplantation (HCT) has met with good success (11,12).
AL amyloidosis
AL amyloidosis occurs when pathogenic light chains unfold
and deposit as insoluble fibrils extracellularly within tissues. It
is found in up to 15% of patients with MM on autopsy (13,14).
In 40% of patients with AL amyloidosis, the bone marrow will
have .10% plasma cells, although only 10% will meet other
criteria for MM (15). Amyloid fibrils may deposit within any
organ, but most commonly affect the kidneys, heart, liver, and
peripheral nervous system.
Patients often present with fatigue, weight loss, and nephrotic
syndrome. The clinical characteristics of patients with biopsy-
proven renal amyloidosis were described in a retrospective review
of 84 patients at the Mayo Clinic (15). The median age at di-
agnosis was 61 years, and 62% were male. The median serum
creatinine on presentation was 1.1 mg/dL. The majority of pa-
tients had nephrotic syndrome (86%) with a median 24-hour
protein loss of 7 g/day. RRT was eventually required in 42% of
patients, and median survival after starting dialysis was less than
1 year. In general, cardiac involvement occurs in nearly one-third
of patients and portends a poor prognosis.
AL amyloid presents as an amorphic hyaline substance
within the mesangium, glomerular basement membranes, and
vessel walls. Mesangial involvement may be diffuse or nodular.
Amyloid stains positive for Congo red and reveals a charac-
teristic apple-green birefringence under polarized light. Im-
munofluorescence staining reveals the underlying monotypic
light chain, which has a l: k ratio of 6:1. Electron microscopy
demonstrates nonbranching randomly oriented 8- to 10-nm
fibrils (Figure 3) (8). Amyloid deposits may appear as sub-
epithelial spikes along the basement membrane similar to
membranous nephropathy.
Treatment with high-dose melphalan followed by HCT
increases hematologic response and overall median survival
(16). Improvement in renal function highly correlates with
increased survival (17).
Treatment of cast nephropathy
General measures
Volume resuscitation to assure optimum hemodynamic
support and adequate urine output (;3 L/day) are of critical

American Society of Nephrology Onco-Nephrology Curriculum 3

Figure 3. Pathology of kidney AL amyloidosis. (A) There is extensive global mesangial and segmental glomerular capillary wall
deposition of acellular, PAS-negative amyloid deposits. For comparison, the hyaline casts depicted are PAS positive (3,4003). (B) By
definition, amyloid deposits should be Congo red positive (i.e., stain red). The figure shows global glomerular and extensive interstitial
Congo red–positive amyloid. (3,2003). (C) Congophilic amyloid deposits characteristically show an apple-green birefringence when
viewed under polarized light (3,2003). (D) On immunofluorescence, amyloid deposits appear smudgy and only stain for one of the light
chains. The figure shows global mesangial and segmental glomerular capillary wall staining for l (3,4003). Staining for k was negative
(not shown). (E) A distinctive feature of kidney AL amyloidosis is glomerular amyloid spicules, which result from parallel alignment of
amyloid fibrils in the subepithelial space perpendicular to the glomerular basement membrane (electron microscopy, 320,0003). (F) On
high magnification, amyloid fibrils appear haphazardly oriented and measure between 7 and 12 nm in diameter (electron microscopy,
326,0003). AL, immunoglobulin light chain; PAS, periodic acid–Schiff. Reprinted from reference 8, with permission of the Elsevier
Science and Technology Journals.

importance in the initial management. Based on experimen-
tal evidence that furosemide promotes intratubular cast
formation by increasing sodium delivery to the distal tubule,
the use of loop diuretics should be avoided unless there is
volume overload. Hypercalcemia should be aggressively
treated because it can lead to renal vasoconstriction, volume
depletion, and enhanced cast formation. It has been sugges-
ted that urinary alkalinization decreases cast formation by
reducing the net positive charge of FLCs and the interaction
with THP (18). However, there is no clinical data supporting
this approach. Given the risk of causing renal calcium pre-
cipitation in the setting of hypercalcemia, urinar y
alkalinization cannot be recommended. Colchicine was
shown to reduce cast formation through decreasing THP
secretion and binding in rats, but human studies have
been disappointing (19,20).
Chemotherapy and stem cell transplantation
The key to treating myeloma cast nephropathy is rapid
reduction in FLC concentrations. An early decrease in FLC
levels is associated with the highest rate of renal recovery. In
severe AKI due to cast nephropathy, a 60% reduction in FLC
levels by day 21 after diagnosis is associated with renal recovery
in 80% of cases (21). Previous studies with conventional

4 Onco-Nephrology Curriculum American Society of Nephrology

chemotherapy protocols demonstrated that high-dose dexa-
methasone rapidly reduced FLCs. Newer, novel agents such as
thalidomide and the proteasome inhibitor, bortezomib, also
rapidly lower FLC concentrations; this has been referred to as
“renoprotective chemotherapy.”
Significant improvement in renal dysfunction has been
reported for MM patients treated with bortezomib-based
regimens (22–24). Reversal of renal dysfunction with borte-
zomib may be more frequent and rapid than with other agents,
based on observational analysis. No dose adjustment for renal
function is necessary for bortezomib.
Thalidomide and lenalidomide are two related chemo-
therapeutic agents commonly used in the treatment of MM.
Lenalidomide dose must be adjusted for renal dysfunction
(25). Thalidomide is not dependent on renal function for
clearance and does not require dose adjustment for renal
function; however, it may predispose to hyperkalemia in the
setting of renal failure (26,27). Regimens with thalidomide or
lenalidomide have shown superior effectiveness to traditional
therapy with alkylating agents in terms of reversing renal dys-
function in MM; these agents may be nearly as effective as
bortezomib regimens (28). Their effects are likely due to rapid
lowering of serum FLC levels.
Hematopoietic stem cell transplantation is an important
and potentially curative therapy in MM; however, patient
selection criteria are stringent, and significant renal dysfunc-
tion has traditionally excluded patients from transplantation.
Recent studies have shown that HCT may be safe and effective
in highly selected patients with renal failure (29).
Extracorporeal removal of free light chains
Light chains are small-molecular-weight proteins. k light
chains usually circulate as monomers with a molecular weight
of 22.5 kDa, whereas l light chains are typically dimeric with a
molecular weight of 45 kDa (30). Because of their size, there
has been a keen interest in the use of extracorporeal therapy
as a means of FLC removal.
A. Therapeutic plasma exchange (TPE):
Several small trials initially suggested that TPE was effective in rapidly
lowering FLC concentrations and improving renal function. How-
ever, these studies were small, single center, and underpowered. The
largest randomized controlled trial of TPE did not demonstrate any
benefit in patients with cast nephropathy (31). This study assessed the
benefit of five to seven TPE sessions in 104 patients (30% were di-
alysis requiring) with presumed cast nephropathy (not all patients
had biopsy confirmation). There was no difference in the two groups
with respect to the composite outcome of death, dialysis, or reduced
renal function at 6 months. This lack of benefit may be related to the
volume of distribution of FLCs. Based on their molecular weights,
85% of light chains are confined to the extravascular space (32).
Therefore, a traditional 2-hour TPE session would be ineffective in
removing significant amounts of FLCs because of the excessive re-
bound effect. Most of the previous trials were performed prior to the
availability of bortezomib-containing regimens. In a recent study of
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14 patients with presumed myeloma kidney treated with bortezomib
and TPE, 12 had complete or partial renal response by 6 months;
however, there were no control patients (33). Although there is still
interest in TPE as a therapy for cast nephropathy, its routine use
cannot be recommended based on the current evidence.
B. High cutoff hemodialysis (HCO-HD):
More recently interest has developed for another method of ex-
tracorporeal removal of FLCs: HCO-HD. In this technique, a
hemofilter with a large pore size (45 kDa) is used for extended
periods of time to remove FLCs.
In the largest study of dialysis dependent renal failure secondary to
MM, 67 patients were treated with HCO-HD and chemotherapy
(34). Only 57% of patients had a renal biopsy, of which 87% had
cast nephropathy. Most patients (85%) received combination
chemotherapy with dexamethasone and either bortezomib or
thalidomide. The median number of HCO-HD sessions was 11,
and all patients had extended (.4 hour) treatments. Overall, 63%
of the patients became dialysis independent. The factors that
predicted renal recovery were the degree of FLC reduction at days
12 and 21 and the time to initiating HCO-HD. Unfortunately, this
trial did not have a control group to assess the benefit of HCO-HD
compared with renoprotective chemotherapy alone.
It is not known whether HCO-HD offers any additional benefit
over current chemotherapeutic regimens. Randomized controlled
trials proving the benefit of adding HCO-HD to patients with cast
nephropathy treated with current chemotherapy will be necessary
before its routine use can be recommended.
LEUKEMIA AND LYMPHOMA
The development of kidney disease is common in patients with
lymphoma and leukemia. As with all hospitalized patients,
those with lymphoma and leukemia are at risk for developing
AKI from hypotension, sepsis, or administration of radio-
contrast, antifungal, and antibacterial agents. With the pres-
ence of cancer, renal injury can also result from chemotherapy,
immunosuppressive drugs, hematopoietic stem cell trans-
plantation, or tumor lysis syndrome. Furthermore, patients
are at risk for renal syndromes specific to the presence of
lymphoma or leukemia including various forms of paraneo-
plastic glomerulopathies, electrolyte disorders, urinary tract
obstruction, lysozymuria, leukostasis, and infiltration of renal
parenchyma (Table 2). Several of these manifestations are
discussed elsewhere in the Curriculum.
Lymphomatous infiltration
Background
Renal involvement in lymphoma is often clinically silent so
patients can present with slowly progressive CKD attributed to
other etiologies. Therefore, a high index of suspicion is needed
to make a diagnosis. Patients may present with AKI, but this is
rare and is most commonly seen in highly malignant and
Onco-Nephrology Curriculum 5
Table 2. Kidney manifestations of lymphoma and leukemia
Comorbid factors
Sepsis and shock
Hypotension
Volume depletion
Radiocontrast administration
Chemotherapeutic agents
Anti-infective agents
Drug- induced tubulointerstitial nephritis
Hematopoietic stem cell transplantation
Radiotherapy
Disease-related factors
Tumor lysis syndrome
Thrombotic microangiopathy
Malignancy-associated hypercalcemia
Paraneoplastic glomerulopathies
Urinary tract obstruction
Parenchymal infiltration
Lysozymuria
Leukostasis
disseminated disease (35–38). Other presentations include
proteinuria in both the nephrotic and nonnephrotic range,
as well as a variety of glomerular lesions including pauci-
immune crescentic glomerulonephritis (39). Patients may also
present with flank pain and hematuria.
Although a variety of cancers can metastasize to the kidneys
and invade the parenchyma, the most common malignancies to
do so are lymphomas and leukemia. The true incidence of renal
involvement is unknown because it is usually a silent disease and
only occasionally causes renal impairment. Autopsy studies
suggest renal involvement occurs in 90% of patients with
lymphoma, whereas radiographic evidence is significantly lower.
The cause of impaired renal function from lymphomatous
infiltration is poorly understood. Based on biopsy series, pa-
tients who present with AKI have predominantly bilateral
interstitial infiltration of the kidneys with lymphoma cells and
uniformly have increased renal size on radiographic imaging
(40). These findings suggest that increased interstitial pressure
results in reduced intrarenal blood flow with subsequent renal
tubular injury. Patients who present with proteinuria, on the
other hand, often have intraglomerular infiltration with lym-
phoma (40). It is not known how proteinuria develops in these
cases, but the local release of permeability factors and cyto-
kines has been suggested (41,42).
Diagnosis
The diagnosis of lymphomatous infiltration is necessarily one
of exclusion because more common explanations are often
present. Renal ultrasonography or computed tomography
(CT) scan may reveal diffusely enlarged kidneys sometimes
with multiple focal lesions (Figure 4) (43). However, many
times, radiology will be unrevealing. In a study of 668 con-
secutive patients with lymphoproliferative disease who un-
derwent diagnostic imaging with a CT scan, only 3% with
6 Onco-Nephrology Curriculum
Figure 4. Computed tomography scan of abdomen and pelvis
without radiocontrast showing bilateral kidney enlargement.
Reprinted from reference 43, with permission of the Elsevier
Science and Technology Journals.
non-Hodgkin lymphoma were found to have kidney abnor-
malities (44). Both diffuse enlargement and solitary lesions
were detected. This discrepancy between radiologic and autopsy/
histopathologic results may due to the fact that renal involve-
ment is often indolent and only detectable in histopathologic
examination (Figure 5) (43). Due to increased metabolic activity
within lymphomatous deposits, positron emission tomography
may be a more sensitive imaging technique (45). Although de-
finitive diagnosis depends on renal biopsy, this procedure often
is impossible because of contraindications. In such cases, the
following criteria support the diagnosis of kidney disease due
to lymphomatous infiltration: 1) renal enlargement without ob-
struction; 2) absence of other causes of kidney disease; and 3)
rapid improvement of kidney function after radiotherapy or
systemic chemotherapy.
Treatment
The treatment of lymphomatous involvement of the kidney is
directed at the underlying malignancy. There are numerous
case reports of improvement in renal function after initiation of
antitumor therapy. In indolent malignant disease that is usually
treated by observation alone, kidney involvement is an in-
dication for starting systemic therapy.
Leukemic infiltration
Background
Leukemia cells can infiltrate any organ, and the kidneys are the
most frequent extramedullary site of infiltration. Autopsy
studies reveal that 60%–90% of patients have renal involve-
ment (46). On biopsy, cells are usually located in the renal
interstitium, although occasional glomerular lesions are noted
(47). Increased interstitial pressure leads to vascular and tu-
bular compression and subsequent tubular injury. Occasional
nodular lesions are found, but this is more common with
lymphoma.
American Society of Nephrology
Figure 5. (A) Kidney biopsy stained with hematoxylin and eosin at 6033 magnification. (B) Tissue stained with B cell–specific
marker anti-CD38 at 20033 magnification. Reprinted from reference 43, with permission of the Elsevier Science and Technology
Journals.
Clinical Features
Leukemic infiltration of the kidneys is often an indolent and
clinically silent disease. Most often it is incidentally noted after
autopsy or by detection of renal enlargement on ultrasound or
CTscan. Although uncommon, many cases of AKI attributable
to leukemic infiltration have been described (48–50). Patients
may also experience hematuria or proteinuria. Occasionally
renal enlargement is accompanied by flank pain or fullness.
There are also reports of patients with chronic lymphocytic
leukemia who develop AKI from leukemic infiltration and are
infected with polyomavirus (BK) (51). Urine from patients
demonstrates viral inclusions in tubular cells (“decoy” cells)
and blood is positive for BK viral DNA. Therefore, in leukemia
patients with AKI considered due to leukemic infiltration,
evidence for coexisting BK virus infection should be sought.
Diagnosis
The diagnosis of leukemia infiltration as a cause of AKI
requires a high level of vigilance because it is often clinically
silent, and leukemic patients usually have multiple alternative
explanations for renal injury. A presumptive diagnosis can be
made if there is no other obvious cause of AKI, bilateral renal
enlargement is demonstrated radiographically, and there is
prompt improvement in renal function after chemotherapy.
Screening for leukemic infiltration with radiographic imaging
is not revealing. In a study of 668 consecutive patients with
lymphoproliferative disease who underwent diagnostic imag-
ing with a CT scan, only 5% with leukemia were found to have
kidney abnormalities (45). As with lymphoma, this discrep-
ancy between radiologic and autopsy/histopathologic results
may be due to the fact that renal involvement is often indolent
and only detectable during histopathologic examination.
Treatment
Treatment is directed by the type of leukemia. Although some
patients do not recover, in the majority of cases, renal function
does improve as the leukemia responds to systemic treatment.
American Society of Nephrology
Lysozymuria
Lysozyme is a cationic protein produced by macrophages and
monocytes and released in response to bacterial infection. It is
freely filtered by the glomerulus and reabsorbed by the
proximal tubule. In certain leukemias, clonal expansion leads
to an excessive production of lysozyme and subsequent
proximal tubular injury and AKI (52). Damage to the proxi-
mal tubule reduces reabsorption and can result in Fanconi
syndrome and nephrotic range proteinuria. The presence of
lysozymuria can be confirmed by detection of an increased g
globulin level on serum and urine protein electrophoresis with
immunofixation negative for monoclonal gammopathy (53).
Treatment is directed at the underlying malignancy.
Leukostasis
Patients with myeloid leukemia and exceedingly high white
blood cell counts (usually in excess of 100,000 cells/mm3) can
develop organ dysfunction due to intravascular aggregation of
leukemic cells. The pulmonary and cerebral circulations are
the most severely affected, although there are case reports of
patients developing AKI (54,55). Leukemic cells occlude the
peritubular and glomerular capillaries, thereby reducing GFR.
Patients may be oliguric, but their renal function often im-
proves with therapeutic leukopheresis or chemotherapy.
Leukostasis is thought to result from the abnormal morphology
of blast cells and the hyperviscocity of the serum. It has been
described in both acute and chronic leukemia. Treatment is
directed at treatment of the malignancy with appropriate che-
motherapeutic regimens; in severe cases, therapeutic leuko-
pheresis can rapidly lower cell counts.
CONCLUSION
Numerous kidney diseases are associated with hematologic
malignancies unique to this population (Tables 1 and 2). The
most common cause of kidney injury in MM patients is cast
nephropathy (myeloma kidney). Rapid reduction of
Onco-Nephrology Curriculum 7
circulating free light chains with newer “renoprotective che-
motherapy” can reverse renal failure in the majority of cases.
Although infiltration of the kidneys by leukemia or lymphoma
is almost universal histologically, clinical renal disease is un-
common. Given the myriad of potential kidney insults in these
patients, a high index of suspicion is necessary to diagnose
infiltration as the cause of renal dysfunction.
TAKE HOME POINTS
c Cast nephropathy is the most common cause of renal failure in patients
with multiple myeloma.
c Rapid lowering of free light chains with “renoprotective” chemotherapy
can reverse renal failure from cast nephropathy in the majority of cases.
c Based on current evidence, extracorporeal removal of free light chains
with either therapeutic plasmapheresis or HCO hemodialysis cannot be
recommended.
c Leukemic and lymphomatous infiltration of the kidneys is common on
autopsy, although it is usually not clinically apparent.
c Enlarged kidneys on imaging and resolution of AKI after therapy with
systemic chemotherapy or radiation support the diagnosis of kidney
infiltration.
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Onco-Nephrology Curriculum 9
REVIEW QUESTIONS
1. An 80-year-old patient with multiple myeloma presents
with serum uric acid of 12.0 mg/dL, serum calcium of 11.0
mg/dL, and a phosphate of 8.1 mg/dL. Serum creatinine is
4.0 mg/dL, and free l light chains are 3,700 mg/L. Which
ONE of the following therapies is contraindicated in this
patient?
a. Urinary alkalinization
b. Intravenous saline
c. Rasburicase
d. Allopurinol
Answer: a is correct. There is a lack of evidence to support
the use of urinary alkalinization to decrease cast formation by
reducing the net positive charge of FLCs. In addition, there is
an increased risk of renal calcium precipitation with the pres-
ence of hypercalcemia.
2. A 57-year-old man with no medical history is diagnosed
with chronic lymphocytic leukemia with Richter’s trans-
formation and presents to the emergency room with cre-
atinine of 3.61 mg/dL and white blood cell count of 20,000/
mm3. The patient has undergone a renal ultrasound in-
dicating slightly enlarged kidneys 13 cm bilaterally. On
examination he was noted to have hepatosplenomegaly.
Urinalysis was negative for proteinuria and hematuria. He
is planned for chemotherapy pending a renal consult for
his rise in creatinine. Which one of the following likely
explains his renal injury?
a. Urinary obstruction related to retroperitoneal lymph-
adenopathy
b. Tumor lysis syndrome
c. Leukemic infiltration of the kidney
d. Membranoproliferative glomerulonephritis with C3
and monoclonal immunoglobulin deposition
Answer: c is correct. It is likely leukemic infiltration in
the setting of enlarged kidney and hepatosplenomegaly with
the lack of other possible etiologies for the patient’s renal
dysfunction.
3. A 74-year-old man with chronic myelomonocytic leuke-
mia with a long-standing history of hypertension and
hyperlipidemia is seen in the clinic. Peripheral blood
monocyte count is .1,000/mm3, and splenomegaly is
noted. His creatinine has started to rise in the last 6 months
to 2.0 mg/dL from a baseline of 1.3 mg/dL. Urinalysis in-
dicated 31 protein and 31 glucose. His labs included the
following: white blood cells, 50,000/mm3; hemoglobin, 9.0
g/dL; platelets, 60,000/mm3; serum potassium, 3.0 mEq/L;
calcium, 8.0 mg/dL; phosphorus, 1.8 mg/dL; serum glu-
cose, 80 mg/dL. Renal ultrasound showed normal size
kidneys and no hydronephrosis. Which ONE of the fol-
lowing is the likely cause of this patient’s renal dysfunction?
10 Onco-Nephrology Curriculum
a. Infiltrative disease secondary to underlying leukemia
b. Membranous glomerulopathy secondary to neoplasm
c. Renal vein thrombosis
d. Lysozyme-induced kidney injury
Answer: d is correct. Lysozyme-induced kidney injury has
been underdiagnosed and underrecognized. Uncontrolled
production of lysozyme secondary to underlying malignancy
predisposes the patient to the damage to the proximal tubule
reduces reabsorption of electrolytes and can result in Fanconi
syndrome and nephrotic range proteinuria. A clue to Fanconi
syndrome is glycosuria with normal serum glucose level.
On electron microscopy, the kidney biopsies have shown an
increase in number and size of lysosomes in the proximal
tubules.
4. A 56-year-old woman with a history of diabetes and hy-
pertension (HTN) presented to the hospital with AKI,
calcium of 12.0 mg/dL, hemoglobin of 10.0 g/dL, and se-
rum albumin of 3.5 g/dL. Urinalysis revealed a specific
gravity 1.015 with trace protein on dipstick examination
and occasional granular cast on microscopic examination.
Renal ultrasonography revealed normal-sized kidneys
without hydronephrosis. Creatinine was noted to be at 5
mg/dL, and blood urea nitrogen was 82 mg/dL with a
normal baseline 6 months ago. Because there was a high
suspicion for multiple myeloma, the patient had a serum
free light chain (FLC) assay to determine monoclonality,
and the free serum l light chains were 1,500 mg/L. Which
of the following treatments is indicated for AKI due to cast
nephropathy?
a. Chemotherapy
b. Hemodialysis using dialyzers that have a high-molecular-
weight cutoff
c. Plasma exchange therapy
d. All of the above
Answer: a is correct. Based on the current evidence, per-
forming plasma exchange and high cutoff hemodialysis to
treat cast nephropathy cannot be recommended. Significant
and rapid reductions in FLC concentrations using “reno-
protective chemotherapy” have been shown of benefit in pre-
serving renal function.
5. A 63-year-old man with a medical history of well-controlled
diabetes and hypertension presents with a creatinine of 2.0
mg/dL, weight loss, fatigue, edema, and worsening periph-
eral neuropathy. He was noted to have a serum albumin level
of 3.0 g/dL, and spot urine protein to creatinine ratio of 2 g,
with no red blood cells in the urinalysis. Liver function
studies were normal. He had a negative skeletal survey, and a
bone marrow biopsy showed normal cellularity with 1%
plasma cells. Serum protein electrophoresis indicated IgA l
M-protein. Due to the possibility of amyloidosis, the patient
underwent a kidney biopsy which showed a mesangial area
expanded by amyloid fibrils. If the patient had AL-type
American Society of Nephrology
 amyloidosis, what is the most appropriate intervention(s)
that would improve overall survival?
a. Chemotherapy to reduce monoclonal protein over-
production
b. Plasma exchange to reduce circulating FLC levels
c. High-dose melphalan followed by autologous hema-
topoietic stem cell transplant
d. Hemodialysis using dialyzers with high-molecular-
weight cutoff
American Society of Nephrology
e. Chemotherapy plus extracorporeal removal of the Ig
FLC
Answer: c is correct. Based on retrospective studies, pa-
tients with AL amyloidosis whom underwent stem cell trans-
plant have been shown to have improved overall survival and
improved quality of life compared with those undergoing
chemotherapy alone. There is no role for plasma exchange
or hemodialysis with a high cutoff filter in the treatment of
amyloidosis.
Onco-Nephrology Curriculum 11