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Cytostatic drug and radiation
associated renal lesions
Heinz Regele
Department of Pathology
Cytostatic drug and radiation associated renal lesions
Radiation
Clinical: Acute and/or chronic renal failure
Histology: Radiation nephritis/nephropathy
Cytostatic drugs
Cisplatin
(Ifosfamide)
Clinical: Acute and/or chronic renal failure
Histology: Tubulointerstitial injury
Renal injury in cancer treatment
Radiation
Clinical: Acute and/or chronic renal failure
Histology: Radiation nephritis/nephropathy
Cytostatic drugs
Cisplatin
(Ifosfamide)
Clinical: Acute and/or chronic renal failure
Histology: Tubulointerstitial injury
Bisphosphonates
Pamidronate, Zoledronate…
Clinical: NS, acute or chronic renal failure
Histology: Glomerular injury and/or tubular injury
Targeted therapies
VEGF blockade
Tyrosine Kinase Inhibitors (TKI)
Clinical: Proteinuria, acute renal failure
Histology: Glomerular injury
Radiation induced kidney lesions
•TMA like changes in glomeruli and arteries:
GBM double contours, mucoid intimal swelling
•Acute tubular injury
•Glomerular scarring
•Intimal fibrosis
•Interstitial fibrosis and tubular atrophy
Radiation nephropathy more appropriate than radiation nephritis
Radiation nephropathy
Diagnostic challenges
Long latency phase after exposure
Clinical signs become detectable after months or
years
•
months
• Chronic radiation nephropathy:
Acute radiation nephropathy:
6-12
2-10 years (with or without acute phase)
Diagnostic features are non-specific
Clinical:
reduced GFR
Histology:
and chronic tubular injury,
Hypertension, proteinuria, edema, urinary casts,
TMA like changes in glomeruli and arteries, acute
glomerular scarring, intimal fibrosis, interstitial
fibrosis might be due to many
RT is frequently combined with other nephrotoxic agents/conditions
other types of injury
Concomitant cytostatic drug therapy
Effects of cytostatic drugs, antibiotics or GvHD might aggravate effects of TBI especially
after BMT
Kidney injury is dose dependent
Dawson LA, Int J Rad Oncol Biol Phys 2010
Schematic risk estimation for kidney injury in
partial kidney radiation therapy
Dawson LA, Int J Rad Oncol Biol Phys 2010
Renal injury by radiolabeled peptides and
antibodies
Radionuclide labeled small proteins
Somatostatin analogs (octreotide):
Neuroendocrine tumors (NET)
Upcoming new agents
• Glucagon-like peptide 1 receptor (exendin-4):
NET
• Gastrin-releasing peptide receptor (bombesin) :
Breast and prostate cancer
• αvβ3 Integrin (aeg-gly-asp (RGD)):
Proliferating endothelial cells
• CCK2 (gastrin) receptor (gastrin-1):
Medullary thyroid carcinoma
Pool SE, Sem Nucl Med 2010
Hydrophilic radiolabeled peptides are excreted mainly via the kidneys and are partially
reabsorbed in proximal tubular cells.
Renal retention of therapeutic radionuclides causes a relatively high radiation dose to the
kidneys, which can lead to kidney failure.
Vegt E, J Nucl Med 2010
Cisplatin induced renal injury
Cisplatin and related platinum-based therapeutics are frequently used for the treatment of
testicular, head and neck, ovarian, cervical, non-small-cell lung carcinoma and many other
types of cancer.
Cisplatin nephrotoxicity is a frequent dose limiting side effect which occurs in about one third
of patients undergoing cisplatin treatment.
Clinical
Cisplatin nephrotoxicity is often seen after 10 days of administration with decreasing
glomerular filtration rate, increased serum creatinine, and reduced serum magnesium and
potassium levels.
Pathophysiology
Main targets are (predominantly proximal) tubular epithelial cells. Drug induced cell death
occurs via apoptosis and necrosis
Mechanisms of Cisplatin nephrotoxicity
Pabla N, KI 2008, KI 2008
Cisplatin induced renal injury
Histology is non-specific and renal biopsies are rarely performed during early stages.
Renal (tubular) dysfunction may persist over years especially if cisplatin was combined with
ifosfamide.
Chronic cisplatin nephropathy is however not clearly defined. Effects of multimodal therapy
or co-morbidity may be confounders in late biopsies.
Bisphosphonates
Bisphosphonates are inhibitors of osteoclast mediated bone resorption.
They are frequently used in the treatment of post menopausal osteoporosis and against lytic
bone lesions in MM or bone metastases
Only high dose i.v. application of bisphsponates used in malignacy associated bone
disorders is associated with nephrotoxicity
Renal lesions typically occur after several months of treatment indication cumulative injury
which was also demonstrated in experimental animals
Nephrotoxicity of Bisphosphonates
Collapsing FSGS
Acute tubular injury
Pamidronate
Zoledronate
Histology and outcome of Bisphosphonate renal injury
Perazella MA, Kidney Int 2008
Anti-angiogenic cancer treatment
Cook KM, CA Cancer J Clin 2010
Anti-angiogenic cancer treatment
Cook KM, CA Cancer J Clin 2010
Receptor Tyrosine Kinase Inhibitors (rTKI)
(VEGFR inhibiting)
Cook KM, CA Cancer J Clin 2010
Renal side effects of VEGF inhibition
Kappers MHW, J Hypertens 2009
High-grade proteinuria (>3.5g/day) upon VEGF
inhibition
Incidence of high-grade proteinuria with bevacizumab according to dosage and tumor type
Wu S, JASN 2010
Renal lesions during VEGF inhibition
Izzedine H, Eur J of Cancer 2010
Conditional VEGF gene deletion in podocytes
Eremina V, NEJM 2008
VEGF is required for normal GEC function
Eremina V, NEJM 2008
Does VEGF inhibition cause podocyte injury?
Sugimoto H, J Biol Chem 2003
Does VEGF inhibition directly cause podocyte injury?
Studies in whole body and cell specific VEGFR-2 KO mice
Normal glomerular function requires paracrine but not autocrine VEGF-VEGFR-2 signaling
Sison K, JASN 2010
Summary
Renal injury is common in radiation therapy and cytostatic drug treatment especially with
platinum based agents and ifosfamide
Biopsies are rarely performed in these conditions, histologic lesions are non-specific and an
overlap with other pathologies can be diagnostically confounding
I.v. application of bisphosphonates is associated with significant (dose dependent) risk of
glomerular (pamidronate) or tubular (zoledronate) nephrotoxicity
Antiangiogenic therapy targeting VEGF signaling frequently leads to proteinuria and
sometimes cause glomerular TMA.
Clinical and experimental findings in VEGF inhibition might provide clues to the mechanisms
of other types of TMA (preeclampsia…)
Proteinuria and TMA may also be caused by receptor
tyrosine kinase inhibitors (rTKI)