This document discusses renal complications associated with hematologic malignancies and their treatment. It provides 3 key points: 1) Lymphomatous infiltration of the kidneys is a common but under-recognized complication of malignant lymphomas, seen in up to one-third of patients on autopsy. Bilateral symmetrical kidney enlargement is the most common imaging finding. 2) Chemotherapies used to treat hematologic malignancies can cause acute kidney injury through tumor lysis syndrome or direct nephrotoxicity. Ifosfamide, in particular, is associated with proximal tubule dysfunction and Fanconi syndrome. 3) Long-term renal complications of chemotherapy include chronic kidney disease, which may progress even after

1. Onconephrology: B cell
Malignancies and the Kidney
Kenar D. Jhaveri, MD
Associate Professor of Medicine
Renal Division, Hofstra NSLIJ School of Medicine, NY

2. The Diseases
The Chemotherapy

3. Ganguli et al Nat Neph 2015

4. 61 year-old man with a history of B cell chronic
lymphocytic leukemia not on chemotherapy presented
with a rise in serum creatinine from 0.8 mg/dL to 4.1
mg/dL over the last 2 weeks and a WBC count of 103,000.
A kidney sonogram reveals large kidneys.

6. CD20

7.  A common but under-recognized complication of
hematologic malignancies
 696 patients with malignant lymphoma:
◦ 33.5% with lymphomatous infiltration of kidneys
◦ 26% unilateral, 74% bilateral involvement
◦ Only 14% diagnosed before death
 Common imaging findings:
◦ Bilateral symmetrical enlargement of the kidneys
◦ Localized mass or masses in an otherwise normal kidney
Richmond J et al. Am J Med. 1962 Feb;32:184-207

8. Lam AQ and Humphreys BD. Clin J Am Soc Nephrol. 2012 Oct;7(10):1692-700.
Management: treatment of primary malignancy
Lymphomatous Infiltration

9.  Other renal complications to consider in lymphoma
patients:
◦ Ureteral obstruction
◦ Urate nephropathy
◦ Hypercalcemia
◦ Paraproteinemia( cast nephropathy and other paraprotein
diseases can be seen with B cell disease as well and not just
plasma cell diseases)
◦ Drug toxicities
Richmond J et al. Am J Med. 1962 Feb;32:184-207

10.  A 67-year-old Caucasian male was referred for
evaluation of proteinuria, edema and elevated
serum creatinine level.
 Pt. had intermittent history of LE swelling (for nearly
1.5 years) that worsened over the last 3-4 months.
 Three months prior to this evaluation, pt. received a
3-month course of Sulindac for “colonic polyps”.
 Sulindac was discontinued as patient developed
worsening LE edema.

11.  ROS was significant for fatigue, worsening LE edema,
and recent onset arthralgias. No history of gross
hematuria or rash.
 No history of recent travel or sick contacts.
 No history of DM
 Medication on initial evaluation included Aspirin,
Levothyroxine and Simvastatin

12.  Pt. had a normal serum creatinine (1.0) approximately
6 months ago at PMD’s office.
 Lab work done during initial evaluation revealed an
elevated serum creatinine level of 2.6 mg/dL.
 He had CLL ( WC baseline 25-30 since 3 years not
needed to be treated)

13. Month Serum Creatinine Serum Albumin
2010 1.0mg/dl 4.7
2011 1.0mg/dl 4.3
Jan 2014 1.0mg/dl 3.9
March 2014 1.4mg/dl 3.8
April 2014 1.7mg/dl 2.5
May 2014 1.8mg/dl 1.5
July 2014 2.6mg/dl 1.4

14. First Bone Marrow BiopsyFirst Bone Marrow Biopsy
Done 1.3 years ago (April 2013):
•Concurrent chronic lymphocytic leukemia and
MGUS- extensive marrow involvement (70%) of B-CLL
(kappa restricted) in nodular and interstitial patterns.
•In addition there is 10% lambda monoclonal plasma
cells are c/w early evolving myeloma.
•The CLL and myeloma clones appear unrelated as they
have different kappa/lambda clonality.
•Features of osteopenia noted as well.

15. Diff:
•23% N
•73% L
•10% M
• WBC: 32.4 ( 70%L)
• Hgb: 12.4
• Hct: 38.1
• Plt: 324
Free light chains:
Kappa: 1.67
Lambda: 7.48
Ratio: 0.22
• Protein /crt trend in the urine
• 3 months ago: 1
• 2 months ago: 4
• 2 weeks ago: 15
• Current: 25
• SIFE: IgG kappa migrating
protein identified
• M spike 0.1g/dl
• Na 136, K 4.1, Cl 106, Co2 16,
BUN 40, Creat 2.6
• Glucose 153, Ca 9.8, Phos 4.8,
Mg 2.0

16. • CLL (65%)
• Lambda light chain plasma cell (5%) and moderately
hypercellular marrow (negative for amyloid)
• Flow: 53% clonal B lymphocytes with CLL - kappa
restricted
• Phenotype and <0.5% lambda monoclonal plasma cells

24. Kappa lc

25. Lambda lc

29. • Amyloidosis, AL lambda type
• Acute Tubular Injury
• Rare Tubular Casts suggestive of Cast Nephropathy
• Severe Glomerulosclerosis with Moderate to Severe IFTA
• Cortical and Perirenal Mononuclear Infiltrate with features
suggestive of Small Lymphocytic Lymphoma/CLL

30.  AL Amyloidosis (lambda)
 Leukemic Infiltration
 Cast Nephropathy

31. Bortezomib based chemo
Bendamustine and Rituximab based chemo
Idelalisib based chemo

34. CLL

35. CLL and the Kidney- Single Center- Mayo Clinic Experience
Existing Renal Disease at the time of CLL diagnosis
At a single center, 7.5% had AKI ( crt greater than 1.5mg/dl)
and 0.7% had a crt >3.0mg/dl
Patients with AKI were statistically had
CLL advanced stage ( Rai III-IV 20.2%, Rai I-II 6.4%, Rai 0 7.0%)
Men > Women
Older age
CD49d positive
Kari G. Rabe et al. Blood 2013;122:5302

36. Acquired Renal Disease at the time of CLL diagnosis
16.1% acquired renal insufficiency (Cr≥1.5 mg/dL) during the course
of their CLL disease course including 43 (2.3%) with peak Cr≥3 mg/dL.
Older age
Males
CD49d
IGHV UM , unfavorable FISH (del17p- or 11q), AP-70+ ,CD38+
Shorter time to first treatment (TTT)(p<0.001) and overall
survival(OS) (P<0.001) was observed among patients with initially
normal creatinine who acquired renal insufficiency.
On MV analysis adjusting for age, sex, and stage at diagnosis,
acquired renal insufficiency remained an independent predictor of
TTT (OR=1.77; p=0.001) and OS (OR=2.67; p<0.001).
Kari G. Rabe et al. Blood 2013;122:5302

37.  MPGN  CLL infiltration
 TMA  MCD
Strati et al. Haematologica 2015
Other less commonly observed
findings were AIN, AL lambda
amyloidosis, light chain cast
nephropathy, membranous GN
and mesangial proliferative GN.
Strati P et al. Haematologica 2015

38.  33 patients at Mayo Clinic with Amyloidosis and CLL
 61% had AL Amyloidosis and 39% had non-AL Amyloidosis
 Of the AL Amyloidosis cohort, 4 had the same clone of
light chain as found in the CLL and another 6 had different
clones
 Treatment was aimed at either plasma cells, B cells or
both.
Kourelis T et al. AJH 2013Kourelis TV et al. Am J Hematol. 2013

39. Kourelis T et al. AJH 2013Kourelis TV et al. Am J Hematol. 2013

40. Kourelis T et al. AJH 2013Kourelis TV et al. Am J Hematol. 2013

41.  Of all the lymphoid malignancies, MCD has been classically associated
with Hodgkin’s lymphoma
Lien, Y.-H. H. & Lai, L.-W. Nat. Rev. Nephrol. 2010

42. The association between Hodgkin’s disease and albuminuria was
described by Galloway in 1922
Since then, several solid tumors & hematological malignancies have
been associated with various glomerular pathology & diseases

43. Ganguli et al Nat Neph 2015

44.  A 42-year-old man presented with 3 months of lethargy, malaise, intermittent
low-grade fevers, and a 10-kg weight loss. On examination, his temperature was
38.7 , heart rate 92 bpm, and blood pressure 96/62 mmHg. His conjunctivae◦
were pale and mucous membranes dry. He had tender lymphadenopathy in both
axillae, in the groin, and on neck exam in the posterior cervical chain. On
abdominal examination, his liver span was slightly increased and tender, and a
spleen tip was palpable at the level of the umbilicus. Extremities revealed 2+
dependent edema, scattered petechiae, and 2+ distal pulses. Laboratory testing
identified potassium 6.6 mEq/L, bicarbonate 16 mEq/L, anion gap 22, creatinine
5.8 mg/dL, albumin 3.1 mg/dL, calcium 5.9 mg/dL, phosphate 18.7 mg/dL, and uric
acid 21.3 mg/dL. Blood counts showed a white blood count (WBC) of 125 K with
abundant blasts, hemoglobin 7.2 mg/dL, and platelets 17 K. Urinalysis
demonstrated a specific gravity of 1.012, pH 5.5, 1+ protein and 2+ blood, and
sediment with degenerating tubular cells and amorphous phosphate crystals.
Because of progressive kidney failure, hyperkalemia, and dropping urine output in
the setting of TLS, urgent dialysis was initiated.

46. Incidence of Tumor Lysis Syndrome Varies with Type of Hematologic
Malignancy
Reprinted from Adv. Chronic Kidney Dis. 21, 18–26, Wilson, F. P. & Berns, J. S. Tumor lysis syndrome:
new challenges and recent advances. Copyright © 2014, with permission from Elsevier
Wilson FP and Berns JS. Adv Chronic Kidney Dis 21:18-28, 2014

47. Metabolic pathways involved in uric acid metabolism and tumor lysis syndrome
Wilson FP and Berns JS. Adv Chronic Kidney Dis 21:18-28, 2014

48. Volume expansion
Forced diuresis?( when and why?)
Allopurinol
Rasburicase
Dialysis ( hemodialysis vs CRRT)

49.  Allopurinol
 Rasburicase
 Hydration

51.  Fludarabine
 Pentostatin
 Alkylating agents( chlorambucil, cyclophosphamide,
bendamustine, ifosfamide)
 MTX
 Anthracyclines

52.  Hemorrhagic cystitis
 No tubular injury
 SIADH( resolves after 24 hours of discontinuation)

53.  Lymphoid malignancies
 Neurotoxicity and Nephrotoxicity -- TMA classically
seen with this agent
 4mg/m2
per week  renal injury
Margolis et al Sem Oncology 2000
Grever MR et al Blood 1983

54. Shirali A, Perazella M, ACKD Jan 2014

55.  Mr. Fos is a 68 Y old male with refractory non Hodgkin’s
lymphoma. The patient has a baseline SCr. of 1.3mg/dL and
bland urine now presents with AKI getting RICE protocol. Post-
treatment patient developed rising SCr; glucosuria, proteinuria,
hypokalemia, metabolic acidosis and hypophosphatemia.
Despite d/c of chemotherapy, the patient’s renal insufficiency
progressed and he required dialysis 10 months after last dose of
chemotherapy.
 WHAT IS THE NEPHROTOXIC drug in RICE?

56. H
L 0.0
2.5
5.0
7.5
10 .0
12 .5
J a n 2 009 A pr J ul O c t
C rea tin in e
mg/dl
FE R A TO V IC , S A B A N
C reatinine (m g/dl)

57.  Alkylating agent
 Proximal dysfunction-Fanconi Syndrome
 Most Data in children
◦ Tubulopathy-30%
◦ Clinically significant Fanconi syndrome-5%
 Glucosuria with normal blood glucose levels
 Hypophosphatemia, hypokalemia, metabolic acidosis,
hypouricemia, aminoaciduria
 AKI-usually resolves prior to next course
 Chronic renal disease
◦ Up to 50% suffer some degree of impairment
◦ Average decline in GFR 35ml/min/1.73m2
(51
Cr-EDTA)
◦ Progressive even after IFOS stopped
Skinner R., et al. British Journal of Cancer (2000) 82(10): 1635-1645Skinner R., et al. British Journal of Cancer (2000) 82(10): 1635-1645

58.  Cumulative dose >60-100gm/2
(*)
 Age at treatment 3-5yrs (?)
 Prior or concurrent treatment with cisplatin/carboplatin
 H/o nephrectomy
 Renal irradiation
 Hydronephrosis
Jones D., et al. Pediatr Blood Cancer (2008); 51(6):724-731

59.  Retrospective review
 259 patient
▫Pts who received cisplatin were
excluded
Decline in GFR correlated with
▫ Age (p<0.001)
▫ Carboplatin exposure (p<0.001)
No Correlation with
▫ Ifosfamide dose-(?low overall dose)
▫Aminoglycoside exposure
▫Auto BMT
Latcha S., Flombaum CD. Personal communication, MSKCCLatcha S., Flombaum CD. Personal communication, MSKCC

60. Shirali A, Perazella M. ACKD Jan 2014

61. Mr. Kohl Farabean is a 48 year old with AML who presented to the hospital
with fever and headaches for one week. His neutropenic fever was treated
with intravenous vancomycin, cefepime and voriconazole and oral
acyclovir.
There was no prior kidney disease and on admission the serum creatinine
was 1.15 mg/dL with good urine output. On hospital day 9 re-induction
therapy with “Drug Z” 30 mg/m2
intravenous(IV) daily days 1 to 5 (his first
exposure to this drug) and “Drug Y “(he had previously been treated with
this agent) 2 g/m2
IV daily days 1 to 5 two hours after “Drug Z” was
initiated.
On hospital day 11, AKI was detected with rise in serum creatinine from
0.97 mg/dL prior to initiation of chemotherapy on day 9 to 2.14 mg/dL on
day 11. Urine output decreased and he became anuric on day 11. There was
no laboratory evidence of tumor lysis syndrome. Later on hospital day 11
the serum creatinine increased to 3.56 mg/dL. Hemodialysis was started on
hospital day 12 due to worsening azotemia and anuria.

62.  Drug Z = clofarabine
 Drug Y = cytarabine
Jhaveri KD, Chidella S, Allen S, Fishbane S. Clofarabine induced kidney disease. J Onco
Pharm Pract 2013

63. Type study % patients with renal
insult
Renal injury grade Other
Case report – 1 patient 1 Proteinuria, Aki No biopsy ( reversible)
Phase trials( AML)-112
adults patients
36% rise in creatinine Grade 3( 6%) No biopsy
Phase trials(AML)- 106
adults patients
14-16% Grade 4 No biopsy
FAERS database ( our
review)
29 patients reported No grade reported No biopsy
Kintzel PE, Visser JA, Campbell AD. Clofarabine-associated acute kidney injury and proteinuria. Pharmacotherapy. 2011
Sep;31(9):923.
Kantarjian H et al;. J Clin Oncol. 2010 Feb 1;28(4):549-55
Burnett AK et al. J Clin Oncol, 2010 May 10;28(14):2389-95
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm
accessed January 23, 2013

64.  Rituximab
 Ofatumumab
 Obinutuzumab

65. AIN: Acute interstitial nephritis
HTN: Hypertension
TMA: Thrombotic microangiopathy

66.  Ibrutinib( Bruton’s tyrosine kinase inhibitor)- no
published cases of acute renal disease
 Cases of severe TLS has been reported
 Initial trial– 35% of patients had increases in crt from
baseline.
 5% had Grade >=3 renal failure( one had
hydronephrosis, others had hypotension, and disease
progression)
Wang M Blood 2015

67.  ABT-199/venetoclax– Tumor lysis syndrome( severe
variant)
 Idelalisib( Phosphoinositide 3-kinase delta inhibitor)-
no renal toxicity noted
 Lenolidomide ( immunomodulator)- AIN, fanconi
syndrome
 Anti CTLA4 therapy- AIN, lupus like nephritis
 Pd-1 inhibitor agents ( for lymphoma)- AIN

68.  Antibodies against CTLA-4
 Acute granulomatous interstitial nephritis(5 cases)
 Nephrotic syndrome like lupus nephritis(2 cases)
 Cell mediated immunity related
 Steroids might be useful
Izzedine H et al Investig New Drugs 2014
Fadel F et al. NEJM 2012

70.  In one trial, there was an increased incidence of elevated
creatinine in the nivolumab-treated group as compared to
the chemotherapy-treated group (13% vs. 9%).
 Steroids help resolve the renal dysfunction in 50% of the
cases. It is presumed to be AIN from an immune mediated
process.
 The FDA label has guidelines to start steroids as the
creatinine rises rapidly.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf

71.  Nephritis occurred in 3 (0.7%) patients- 1 was autoimmune nephritis and
2 were AIN
 The time to onset of autoimmune nephritis was 12 months after the first
dose of pembrolizumab(5 months after the last dose) and lasted 3.2
months; this patient did not have a biopsy.
 Acute interstitial nephritis was confirmed by renal biopsy in two patients
with Grades 3-4 renal failure.
 All three patients fully recovered renal function with treatment with high-
dose corticosteroids (greater than or equal to 40 mg prednisone or
equivalent per day) followed by a corticosteroid taper.
www.accessdata.fda.gov/drugsatfda_docs/lab
el/2014/125514lbl.pdf

72. Agent CKD Dialysis
Bendamustine 40-80 GFR on changes,
<40 data limited–
recommend not use
No data
Cyclophosphamide 10-90- no changes
<10%- reduce dose by 25%
Reduce dose by 50% and
after HD
Ifosfamide 45-60, reduce by 20%
30-45, reduce by 25%
<30, reduce by 30%
No data
Fludarabine Reduced dose of 20mg/m2 Administer after HD
Rituximab No dose adjustment No dose adjustment
Idelalisib No data No data
Clofarabine 50% reduced dose No data
Ibrutinib No dose adjustment No data

73. The Diseases
The Chemotherapy
Both are toxic to
the
kidney