Wednesday, March 11, 2015

#NephMadness #OncoRegion Tyrosine Kinase Inhibitor Toxicity Abstracts

Nephrol Dial Transplant. 2009 Feb;24(2):682-5. doi: 10.1093/ndt/gfn657. Epub 2008 Dec 2.

Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib.

Bollée G(1), Patey N, Cazajous G, Robert C, Goujon JM, Fakhouri F, Bruneval P,
Noël LH, Knebelmann B.

Author information:
(1)APHP, Service de Néphrologie Adulte, Hôpital Necker, Paris, France.

Comment in
    Nephrol Dial Transplant. 2009 Jun;24(6):2002-3.

BACKGROUND: Drugs targeting the VEGF pathway are associated with renal adverse
events, including proteinuria, hypertension and thrombotic microangiopathy (TMA).
Most cases of TMA are reported secondary to bevacizumab. It was shown recently
that sunitinib, a small molecule inhibiting several tyrosine kinase receptors,
including VEGF receptors, can also induce proteinuria, hypertension and
biological features of TMA. Case. A 44-year-old woman with a history of malignant
skin hidradenoma was started on sunitinib for refractory disease. She developed
hypertension after 2 weeks and low-grade proteinuria after 4 weeks. Renal
function remained normal, and biological signs of TMA were absent. A renal biopsy
was performed 6 months later as proteinuria persisted, demonstrating typical
features of TMA. The patient was given irbesartan, and sunitinib was continued
for 3 months after diagnosis. Over this period, blood pressure and renal function
remained stable and proteinuria became undetectable.
CONCLUSION: We report on the first case of histologically documented TMA
secondary to sunitinib and provide detailed description of renal histological
involvement. This suggests that all anti-VEGF drugs may share a common risk for
developing renal adverse events, including TMA. Our case highlights the possible
discrepancy between mild clinical manifestation on one hand and severe TMA
features on renal biopsy on the other hand and pleads for large indication of
renal biopsy in this setting. The renin-angiotensin system blockers may be
considered in patients with mild clinical manifestations and in the absence of
therapeutic alternative to anti-VEGF drugs.

PMID: 19054798  [PubMed - indexed for MEDLINE]

Nephrol Dial Transplant. 2014 Feb;29(2):325-32. doi: 10.1093/ndt/gft465. Epub 2013 Dec 2.

All anti-vascular endothelial growth factor drugs can induce 'pre-eclampsia-like syndrome': a RARe study.

Vigneau C(1), Lorcy N, Dolley-Hitze T, Jouan F, Arlot-Bonnemains Y, Laguerre B,
Verhoest G, Goujon JM, Belaud-Rotureau MA, Rioux-Leclercq N.

Author information:
(1)CHU Rennes, Service de Néphrologie, Rennes, France.

BACKGROUND: Specific therapies that target vascular endothelial growth factor
(VEGF) and its receptors have improved the survival of patients with metastatic
cancers, but can induce side effects. Renal side effects (proteinuria,
hypertension and renal failure) are underestimated.
METHODS: The French RARe (Reins sous traitement Anti-VEGF Registre) study
collects data on patients with cancer who had a renal biopsy because of major
renal side effects during treatment with anti-VEGF drugs.
RESULTS: We collected 22 renal biopsies performed 16.2±10.6 months after the
beginning of treatment; of which 21 had hypertension, mean proteinuria was
2.97±2.00 g/day and mean serum creatinine, 134±117 µmol/L. Thrombotic
microangiopathy (TMA) was observed in 21 biopsy specimens, sometimes associated
with acute tubular necrosis (ATN; n=4). TMA histological lesions were more
important than the biological signs of TMA could suggest. Patients with ATN of
>20% had higher serum creatinine levels than those with only TMA (231 versus 95
µmol/L). Nephrin, podocin and synaptopodin were variably down-regulated in all
renal biopsies. VEGF was down-regulated in all glomeruli.
CONCLUSION: This study underlines the importance of regular clinical and
biological cardiovascular and renal checking during all anti-VEGF therapies for
cancer for early detection of renal dysfunction. Collaboration between
oncologists and nephrologists is essential. In such cases, renal biopsy might
help in appreciating the severity of the renal lesions and after
multidisciplinary discussion whether or not it is safe to continue the treatment.

PMID: 24302609  [PubMed - indexed for MEDLINE]

Am J Geriatr Pharmacother. 2007 Dec;5(4):341-4. doi:

Allergic interstitial nephritis possibly related to sunitinib use.

Khurana A(1).

Author information:
(1)Scott & White Memorial Hospital and Clinic, Texas A&M College of Health
Sciences Center, Temple, Texas 76508, USA.

BACKGROUND: Sunitinib is an oral multitargeted inhibitor indicated for the
treatment of renal cell carcinoma.
OBJECTIVE: This report describes a case of allergic interstitial nephritis
possibly related to this agent.
CASE SUMMARY: A 69-year-old female patient with a history of metastatic renal
cell carcinoma after left radical nephrectomy presented to our nephrology clinic
after completing 2 courses of sunitinib therapy. The patient was noted to have
progressive kidney dysfunction with proteinuria, together with peripheral
eosinophilia and eosinophiluria, which developed during the first of 2 cycles of
sunitinib therapy. Her concomitant medications included atenolol,
triamterene/hydrochlorothiazide, amlodipine, and multivitamin tablets, all of
which she had been receiving at stable doses over the previous 2 years. There
were no other over-the-counter medications involved and other possible causes of
interstitial nephritis were excluded. The proteinuria, eosinophilia, and
eosinophiluria worsened with the second course and resolved after sunitinib
discontinuation, which resulted in initial stabilization followed by slight
improvement in kidney function. The Naranjo Adverse Drug Reaction Probability
Scale score for this event was 7, indicating a probable association of the event
with the drug. With clinical improvement after discontinuation of sunitinib and
the presence of a solitary remaining kidney and thrombocytopenia, renal biopsy
was not performed after discussion with the patient. When challenged with a
related agent, sorafenib, the patient experienced worsening of serum creatinine
and increasing eosinophilia, similar to that noted with sunitinib, suggesting
that this event may be a class effect.
CONCLUSIONS: Nephrologists and oncologists should be aware of allergic
interstitial nephritis as an adverse effect related to this agent. Although there
are no current recommendations for monitoring serum creatinine with sunitinib
therapy, we recommend that serum creatinine and white cell count with
differential be checked within 2 weeks of initiation of therapy with sunitinib to
enable earlier diagnosis of this condition and avoid renal damage.

PMID: 18179992  [PubMed - indexed for MEDLINE]

Nephron Clin Pract. 2011;117(4):c312-9. doi: 10.1159/000319885. Epub 2010 Nov 3.

Nephrotoxicities associated with the use of tyrosine kinase inhibitors: a single-center experience and review of the literature.

Jhaveri KD(1), Flombaum CD, Kroog G, Glezerman IG.

Author information:
(1)Division of Nephrology and Hypertension, Weill Cornell Medical Center, New
York, NY, USA.

BACKGROUND: Sunitinib is an oral multitargeted tyrosine kinase receptor inhibitor
(MTKI) used for the treatment of renal cell carcinoma. These small-molecule
agents inhibit signaling through receptor tyrosine kinases such as vascular
endothelial growth factor receptor, platelet-derived growth factor receptor and
cytokine stem cell factor receptor, among others. Although the development of
these novel molecular-targeted agents represents a substantial advance in the
treatment of metastatic cancer, the spectrum of their adverse effects may be
broader than initially predicted.
METHOD: We performed a retrospective chart review of patients who had received
sunitinib and developed renal insufficiency.
RESULTS: We describe 4 patients with renal cell carcinoma and 1 patient with
transitional cell carcinoma treated with sunitinib who experienced various
degrees of nephrotoxicity including hypertension, proteinuria, thrombotic
microangiopathy, and acute and chronic kidney injury which resolved upon
cessation of MTKI.
CONCLUSIONS: Nephrologists and oncologists should be aware of the potential for
toxic renal effects, and we recommend guidelines for early recognition and
treatment of these conditions in patients receiving MTKI.

Copyright © 2010 S. Karger AG, Basel.

PMID: 21051905  [PubMed - indexed for MEDLINE]

Ann Oncol. 2011 Sep;22(9):2073-9. doi: 10.1093/annonc/mdq715. Epub 2011 Feb 10.

Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients.

Marcolino MS(1), Boersma E, Clementino NC, Macedo AV, Marx-Neto AD, Silva MH, van
Gelder T, Akkerhuis KM, Ribeiro AL.

Author information:
(1)School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte,

BACKGROUND: We analyzed the incidence of acute kidney injury and chronic renal
failure in chronic myeloid leukemia (CML) patients using imatinib and
investigated whether there is a relation between duration of imatinib therapy and
decrease in estimated glomerular filtration rate (GFR).
PATIENTS AND METHODS: One hundred five CML patients on imatinib therapy were
enrolled. Creatinine, urea, uric acid, and potassium measurements from imatinib
treatment onset until the end of follow-up (median 4.5 years) were included in
the analysis. GFR was estimated using the Chronic Kidney Disease Epidemiology
Collaboration equation.
RESULTS: During follow-up, 7% of patients developed acute kidney injury;
creatinine levels returned to baseline in only one of them. According to the
regression equation, the mean baseline value of the estimated GFR was 88.9
ml/min/1.73 m(2). Estimated GFR decreased significantly with imatinib treatment
duration; the mean decrease per year was 2.77 ml/min/1.73 m(2) (P < 0.001); 12%
of patients developed chronic renal failure. Age, hypertension, and a history of
chronic renal failure or interferon usage were not significantly related to the
mean decrease in the estimated GFR over time.
CONCLUSION: The introduction of imatinib therapy in nonclinical trial CML
patients is associated with potentially irreversible acute renal injury, and the
long-term treatment may cause a clinically relevant decrease in the estimated

PMID: 21310760  [PubMed - indexed for MEDLINE]

 Leuk Res. 2009 Feb;33(2):344-7. doi: 10.1016/j.leukres.2008.07.029. Epub 2008 Oct2.

Renal failure and recovery associated with second-generation Bcr-Abl kinase inhibitors in imatinib-resistant chronic myelogenous leukemia.

Holstein SA(1), Stokes JB, Hohl RJ.

Author information:
(1)Division of Hematology, Oncology and Blood & Marrow Transplantation,
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.

Tyrosine kinase inhibitors (TKIs) directed against the Bcr-Abl kinase have
revolutionized the treatment of chronic myelogenous leukemia (CML). Relatively
little is known regarding the effects of these agents on the kidney. Clinically,
there have been a handful of reports associating imatinib with acute renal
failure. Preclinical reports indicate that imatinib inhibits signaling pathways
which may play a role in renal injury. We report the case of a patient with
imatinib-resistant CML who developed renal failure after being placed on
dasatinib. When she later became resistant to dasatinib she was switched to
nilotinib. Shortly thereafter, she became dialysis-independent. Second-generation
Bcr-Abl TKIs may influence renal function based on differential inhibition of
related tyrosine kinases.

PMID: 18835038  [PubMed - indexed for MEDLINE]

N Engl J Med. 2006 May 11;354(19):2006-13.

Altered bone and mineral metabolism in patients receiving imatinib mesylate.

Berman E(1), Nicolaides M, Maki RG, Fleisher M, Chanel S, Scheu K, Wilson BA,
Heller G, Sauter NP.

Author information:
(1)Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
10021, USA.

Comment in
    N Engl J Med. 2006 Aug 10;355(6):627; author reply 628-9.
    N Engl J Med. 2006 Aug 10;355(6):627; author reply 628-9.
    N Engl J Med. 2006 Dec 7;355(23):2494-5.
    N Engl J Med. 2006 Aug 10;355(6):628; author reply 628-9.

BACKGROUND: Imatinib mesylate inhibits several tyrosine kinases, including
BCR-ABL, the C-KIT receptor, and the platelet-derived growth factor receptors
alpha and beta, all of which are associated with disease. We observed that
hypophosphatemia developed in some patients with either chronic myelogenous
leukemia or gastrointestinal stromal tumors who were receiving imatinib.
METHODS: We identified 16 patients who had low serum phosphate levels and 8
patients who had normal serum phosphate levels, all of whom were receiving
imatinib. We performed the following biochemical measurements: whole-blood levels
of ionized calcium, plasma levels of intact parathyroid hormone, and serum levels
of total calcium, phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D,
magnesium, and markers of bone formation (bone alkaline phosphatase and
osteocalcin) and bone resorption (N-telopeptide of collagen cross-links);
urinalysis; and phosphate, calcium, and creatinine levels in "spot" urine
RESULTS: Patients in the low-phosphate group (median serum phosphate level, 2.0
mg per deciliter [0.6 mmol per liter]; normal level, >2.5 mg per deciliter [0.8
mmol per liter]) had elevated parathyroid hormone levels and low-to-normal serum
calcium levels, were younger, and were receiving a higher dose of imatinib than
patients in the normal-phosphate group (median level, 3.2 mg per deciliter [1.0
mmol per liter]). Both groups had high levels of phosphate excreted in the urine
and markedly decreased serum levels of osteocalcin and N-telopeptide of collagen
CONCLUSIONS: Hypophosphatemia, with associated changes in bone and mineral
metabolism, develops in a proportion of patients taking imatinib for either
chronic myelogenous leukemia or gastrointestinal stromal tumors. The drug may
inhibit bone remodeling (formation and resorption), even in patients with normal
serum phosphate levels.

Copyright 2006 Massachusetts Medical Society.

PMID: 16687713  [PubMed - indexed for MEDLINE]


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