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 drugsCisplatin Clinical: Acute and/or chronic renal failure

(Ifosfamide) Histology: Tubulointerstitial injury

Renal injury in cancer treatment

Radiation Clinical: Acute and/or chronic renal failure

Histology: Radiation nephritis/nephropathy

Cytostatic drugsCisplatin Clinical: Acute and/or chronic renal failure

(Ifosfamide) Histology: Tubulointerstitial injury

Targeted therapiesVEGF blockade Clinical: Proteinuria, acute renal failure

Tyrosine Kinase Inhibitors (TKI) Histology: Glomerular injury

BisphosphonatesPamidronate, Zoledronate… Clinical: NS, acute or chronic renal failure

Histology: Glomerular injury and/or tubular 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

Long latency phase after exposureClinical signs become detectable after months or

years• Acute radiation nephropathy: 6-12 months• Chronic radiation nephropathy: 2-10 years (with or without acute phase)Diagnostic features are non-specific

Clinical: Hypertension, proteinuria, edema, urinary casts, reduced GFR

Histology: TMA like changes in glomeruli and arteries, acute and chronic tubular injury,

glomerular scarring, intimal fibrosis, interstitial fibrosis might be due to many

other types of injury RT is frequently combined with other nephrotoxic agents/conditions

Concomitant cytostatic drug therapy

Effects of cytostatic drugs, antibiotics or GvHD might aggravate effects of TBI especially after BMT

Diagnostic challenges

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

Vegt E, J 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.

Pool SE, Sem 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

Wu S, JASN 2010

Incidence of high-grade proteinuria with bevacizumab according to dosage and tumor type

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?

Normal glomerular function requires paracrine but not autocrine VEGF-VEGFR-2 signaling

Sison K, JASN 2010

Studies in whole body and cell specific VEGFR-2 KO mice

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

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…)

I.v. application of bisphosphonates is associated with significant (dose dependent) risk of glomerular (pamidronate) or tubular (zoledronate) nephrotoxicity

Proteinuria and TMA may also be caused by receptor tyrosine kinase inhibitors (rTKI)